Assessment of knowledge, attitude and practice of adverse drug reaction reporting among healthcare professionals in secondary and tertiary hospitals in the capital of Pakistan.
Adverse Drug Reactions (ADRs) underreporting is a great challenge to pharmacovigilance. Healthcare professionals should consider ADR reporting as their professional obligation because the effective system of ADR reporting is important to improve patient care and safety. This study was designed to assess the knowledge, attitude, practice and factors associated with ADR reporting by healthcare professionals (physicians and pharmacists) in secondary and tertiary hospitals of Islamabad. A pretested questionnaire comprising of 27 questions (knowledge 12, attitude 4, practice 9 and factors influencing ADR reporting 2) was administered to 384 physicians and pharmacists in public and private hospitals. Respondents were evaluated for their knowledge, attitude and practice related to ADR reporting. Additionally, the factors which encourage and discourage respondents to report ADRs were also determined. The data was analysed by using SPSS statistical software. Among 384 respondents, 367 provided responses to questionnaire, giving a response rate of 95.5%. The mean age was 28.3 (SD = 6.7). Most of the respondents indicated poor ADR reporting knowledge (83.1%). The majority of respondents (78.2%) presented a positive attitude towards ADR reporting and only a few (12.3%) hospitals have good ADR reporting practice. The seriousness of ADR, unusualness of reaction, new drug involvement and confidence in the diagnosis of ADR are the factors which encourage respondents to report ADR whereas lack of knowledge regarding where and how to report ADR, lack of access to ADR reporting form, managing patient is more important than reporting ADR legal liability issues were the major factors which discourage respondents to report ADR. The study reveals poor knowledge and practice regarding ADR reporting. However, most of the respondents have shown a positive attitude towards ADR reporting. There is a serious need for educational training as well as sincere and sustained efforts should be made by Government and Hospital Authorities to ensure proper implementation of ADR reporting system in all of the hospitals.


Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis.
The disruption of the energy or nutrient balance triggers endoplasmic reticulum (ER) stress, a process that mobilizes various strategies, collectively called the unfolded protein response (UPR), which reestablish homeostasis of the ER and cell. Activation of the UPR stress sensor IRE1α (inositol-requiring enzyme 1α) stimulates its endoribonuclease activity, leading to the generation of the mRNA encoding the transcription factor XBP1 (X-box binding protein 1), which regulates the transcription of genes encoding factors involved in controlling the quality and folding of proteins. We found that the activity of IRE1α was regulated by the ER oxidoreductase PDIA6 (protein disulfide isomerase A6) and the microRNA miR-322 in response to disruption of ER Ca2+ homeostasis. PDIA6 interacted with IRE1α and enhanced IRE1α activity as monitored by phosphorylation of IRE1α and XBP1 mRNA splicing, but PDIA6 did not substantially affect the activity of other pathways that mediate responses to ER stress. ER Ca2+ depletion and activation of store-operated Ca2+ entry reduced the abundance of the microRNA miR-322, which increased PDIA6 mRNA stability and, consequently, IRE1α activity during the ER stress response. In vivo experiments with mice and worms showed that the induction of ER stress correlated with decreased miR-322 abundance, increased PDIA6 mRNA abundance, or both. Together, these findings demonstrated that ER Ca2+, PDIA6, IRE1α, and miR-322 function in a dynamic feedback loop modulating the UPR under conditions of disrupted ER Ca2+ homeostasis.


Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives.
Myokines are molecules produced and secreted by skeletal muscle to act in an auto-, para- and endocrine manner to alter physiological function of target tissues. The growing number of effects of myokines on metabolism of distant tissues provides a compelling case for crosstalk between skeletal muscle and other tissues and organs to regulate metabolic homoeostasis. In this review, we summarize and discuss the current knowledge regarding the impact on metabolism of several canonical and recently identified myokines. We focus specifically on myostatin, β-aminoisobutyric acid, interleukin-15, meteorin-like and myonectin, and discuss how these myokines are induced and regulated as well as their overall function. We also review how these myokines may serve as potential prognostic biomarkers that reflect whole-body metabolism and how they may be attractive therapeutic targets for treating muscle and metabolic diseases.


Virtual reality and augmented reality as strategies for teaching social skills to individuals with intellectual disability: A systematic review.
Virtual reality (VR) and augmented reality (AR) programs have proliferated significantly in recent years and they are finding their way into different educational and therapeutic purposes. This systematic review aims at analyzing the virtual reality and augmented reality programs designed to promote the development of social skills in individuals with intellectual disability. Searches were carried out in the Scopus, Science Direct, Springer and Web of Science databases in the period from 2005 to 2020. A total of six articles met the inclusion criteria. A descriptive data analysis was performed. The results show that the clinical profile of the individuals who participated in the interventions is diverse. It can be concluded that there is some scientific evidence that points to the usefulness of VR and AR in the development of intervention programs to improve the social skills of individuals diagnosed with developmental deficits. However, it is necessary to acknowledge methodological limitations such as the lack of control groups, follow-up measures and of generalization of the results.


Does the Application of Heat Gel Pack After Eutectic Mixture of Local Anesthetic Cream Improve Venipuncture or Intravenous Cannulation Success Rate in Children? A Randomized Control Trial.
Needle-related procedures are the most common sources of pain for children in the hospital setting. The most used topical anesthetic, eutectic mixture of local anesthetic (EMLA) cream, may cause transient vasoconstriction. It has been postulated that this vasoconstriction may decrease vein visualization. The application of heat gel pack after removal of EMLA cream in the site of venipuncture counteracts the vasoconstriction, improving vein visualization. We assessed using a prospective randomized controlled trial whether the application of heat gel pack increases the needle procedure success rate. The primary study outcome was procedural success rate at the first attempt. The study enrolled 400 children, 200 of whom applied heat gel pack after removing EMLA (treatment group) and 200 did not (control group). Procedural success rate at the first attempt, vein perception before procedure, procedural pain, and adverse events were recorded in both groups. Eighty-eight percent of the procedures were successful at the first attempt in the treatment group and 89% in the control group (P = 0.876). Vein perception was not significantly different in the 2 groups (P = 0.081). Pain score after the procedure was similar in the 2 groups. This study shows that the application of heat gel pack after removal of EMLA cream does not improve venipuncture or intravenous cannulation success rate.


Transgene expression after adenovirus-mediated retransfection of rat lungs is increased and prolonged by transplant immunosuppression.
Adenovirus-mediated gene therapy has been proposed as a potential treatment modality in lung transplantation. However, to date its utility has been limited by an inflammatory host immune response that not only limits the amount and duration of transgene expression but also obviates successful retransfection. Having previously shown that by administering triple-immunosuppression, as is routine in lung transplantation, we could increase and prolong transgene expression after initial transfection, we hypothesized that transgene expression after retransfection could also be increased and prolonged. Lewis rats underwent intratracheal adenovirus-mediated transfection with the beta-galactosidase gene and were randomized to either the immunosuppression group, receiving daily cyclosporine (INN: ciclosporin), azathioprine, and methylprednisolone, or the control group (no immunosuppression). Five weeks later, rats were similarly retransfected and transgene expression and post-transfection inflammation were evaluated 1, 7, and 14 days after retransfection. After retransfection, immunosuppressed rats had significantly higher levels of transgene expression (P <.001), whereas control rats had virtually no detectable levels. On histologic sections of the lungs, immunosuppressed rats had overall lesser grades of post-transfection inflammation. Transplant immunosuppression attenuates the severe immune response to gene transfer and permits increased, prolonged, and repeated transfection. Retransfection is now achievable in the immunosuppressed lung transplant setting to allow for chronic, repeated administration of gene therapy.


Sexual selection buffers the negative consequences of population fragmentation on adaptive plastic responses to increasing temperatures.
Whether sexual selection facilitates or hampers the ability to plastically respond to novel environments might depend on population structure, via its effects on sexual interactions and associated fitness payoffs. Using experimentally evolved lines of the seed beetle Callosobruchus maculatus, we tested whether individuals evolving under different sexual selection (monogamy vs polygamy) and population spatial structure (metapopulation vs undivided populations) treatments differed in their response across developmental thermal conditions (control, hot or stressful) in a range of fitness and fitness-associated traits. We found that individuals from subdivided populations had lower lifetime reproductive success (LRS) at hot temperatures, but only in lines evolving under relaxed sexual selection, revealing a complex interaction between sexual selection, population structure, and thermal environmental stress on fitness. We also found an effect of population structure on several traits, including fertility and adult emergence success, under exposure to high thermal conditions. Finally, we found a strong negative effect of hot and stressful temperatures in fitness and associated traits. Our results show that population structure can exacerbate the impact of a warming climate, potentially leading to declines in population viability, but that sexual selection can buffer the negative influence of population subdivision on adaptation to warm temperatures.


Nonlinear refractive index of porcine cornea studied by z-scan and self-focusing during femtosecond laser processing.
We have investigated the nonlinear refractive index of ex-vivo pig cornea by a combined approach using the standard z-scan technique on extracted corneas or corneal slices, as well as studying the deviations caused by self-focusing during femtosecond laser processing of the pig eyes. The experiments yield consistently an upper limit of 1.2 MW for the critical power of self-focusing in porcine cornea, and a value of 2 x 10(-19) m(2)/W for its nonlinear refractive index. We also demonstrate that due to this nonlinear refraction the cutting depth of typical fs-laser surgery processing in cornea may depend considerably, albeit in a well controllable way, on the laser parameters.


NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality.
Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta-analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 × 10-6 Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 × 10-5), with combined stages 1 and 2 genome-wide significance of P=5.6 × 10-10 Transethnic meta-analysis further supported the association at rs9980 (P=5.9 × 10-12). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 × 10-8). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.


[Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference].
Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.


Rapid separation of synthetic oligonucleotides on polymer modified capillary surfaces using short-end injection capillary electrophoresis in free solution.
Here we use short-end electrokinetic injection capillary electrophoresis (CE) to investigate the free solution mobility of short strands of double-stranded oligonucleotides (dsODNs) on polymer modified capillaries. Single base pair (bp) resolution (Rs) of dsODNs ranging from 16-20 bp was achieved in free solution on an 8 cm capillary dynamically coated with poly(ethylpyrrolidine methacrylate-co-methyl methacrylate) (PEPyM-co-PMMA) random copolymer. Interestingly, separation of a dsODN mixture containing two 16 bp strands of different sequences resulted in partial resolution (0.52) implying that the free solution mobility of dsODNs was sequence dependent. The single bp resolution achieved for the complementary sequence strands (the sequence of all strands in the mixtures contained the same 16 bp sequence) was improved by up to 37% for separation of dsODNs containing non-complementary sequences. The 16 bp peak was not additive within each mixture, indicating the presence of ODN-ODN interactions. Investigation of these interactions (and ODN-buffer interactions) showed that they can be influenced by the ionic strength and conductivity of the background electrolyte (BGE). Increasing the ionic strength reduced the ODN-ODN interactions and improved the resolution, whereas, increasing the conductivity reduced ODN-buffer interactions, increasing the mobility, at the consequence of promoting ODN-ODN interactions, and hence decreasing the resolution.


Resorcylidene aminoguanidine (RAG) improves cardiac mitochondrial bioenergetics impaired by hyperglycaemia in a model of experimental diabetes.
Diabetes is associated with a mitochondrial dysfunction. Hyperglycaemia is also clearly recognized as the primary culprit in the pathogenesis of cardiac complications. In response to glycation and oxidative stress, cardiac mitochondria undergo cumulative alterations, often leading to heart deterioration. There is a continuous search for innovative treatment strategies for protecting the heart mitochondria from the destructive impact of diabetes. Aminoguanidine derivatives have been successfully used in animal model studies on the treatment of experimental diabetes, as well as the diabetes-driven dysfunctions of peripheral tissues and cells. Considerable attention has been paid particularly to β-resorcylidene aminoguanidine (RAG), often shown as the efficient anti-glycation and anti-oxidant agent in both animal studies and in vitro experiments. The aim of the present study was to test the hypothesis that RAG improves oxidative phosphorylation and electron transport capacity in mitochondria impaired by hyperglycaemia. Diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of streptozotocin (70 mg/kg body weight). Heart mitochondria were isolated from healthy rats and rats with streptozotocin-diabetes. Mitochondrial respiratory capacity was measured by high resolution respirometry with the OROBOROS Oxygraph-2k according to experimental protocol including respiratory substrates and inhibitors. The results revealed that RAG protects the heart against diabetes-associated injury by improving the mitochondrial bioenergetics, thus suggesting a possible novel pharmacological strategy for cardioprotection.


Systematic Review and Meta-Analyses of Word Production Abilities in Dysfunction of the Basal Ganglia: Stroke, Small Vessel Disease, Parkinson's Disease, and Huntington's Disease.
Clinical populations with basal ganglia pathologies may present with language production impairments, which are often described in combination with comprehension measures or attributed to motor, memory, or processing-speed problems. In this systematic review and meta-analysis, we studied word production in four (vascular and non-vascular) pathologies of the basal ganglia: stroke affecting the basal ganglia, small vessel disease, Parkinson's disease, and Huntington's disease. We compared scores of these clinical populations with those of matched cognitively unimpaired adults on four well-established production tasks, namely picture naming, category fluency, letter fluency, and past-tense verb inflection. We conducted a systematic search in PubMed and PsycINFO with terms for basal ganglia structures, basal ganglia disorders and language production tasks. A total of 114 studies were included, containing results for one or more of the tasks of interest. For each pathology and task combination, effect sizes (Hedges' g) were extracted comparing patient versus control groups. For all four populations, performance was consistently worse than that of cognitively unimpaired adults across the four language production tasks (p-values < 0.010). Given that performance in picture naming and verb inflection across all pathologies was quantified in terms of accuracy, our results suggest that production impairments cannot be fully explained by motor or processing-speed deficits. Our review shows that while language production difficulties in these clinical populations are not negligible, more evidence is necessary to determine the exact mechanism that leads to these deficits and whether this mechanism is the same across different pathologies.


Charge fluctuations in nanoscale capacitors.
The fluctuations of the charge on an electrode contain information on the microscopic correlations within the adjacent fluid and their effect on the electronic properties of the interface. We investigate these fluctuations using molecular dynamics simulations in a constant-potential ensemble with histogram reweighting techniques. This approach offers, in particular, an efficient, accurate, and physically insightful route to the differential capacitance that is broadly applicable. We demonstrate these methods with three different capacitors: pure water between platinum electrodes and a pure as well as a solvent-based organic electrolyte each between graphite electrodes. The total charge distributions with the pure solvent and solvent-based electrolytes are remarkably Gaussian, while in the pure ionic liquid the total charge distribution displays distinct non-Gaussian features, suggesting significant potential-driven changes in the organization of the interfacial fluid.


Differentiation of semantic dementia and Alzheimer's disease using the Addenbrooke's Cognitive Examination (ACE).
The Addenbrooke's Cognitive Examination (ACE) is a simple diagnostic tool bridging the gap between the very brief Mini Mental State Exam (MMSE) and much longer test batteries used by neuropsychologists which has proven extremely popular internationally. We aimed to assess the ability of the ACE to differentiate semantic dementia (SD) from Alzheimer's disease (AD). The ACE was administered to three groups: SD patients (n = 40) and two separate groups of AD patients (n = 40 in each), matched for overall ACE or MMSE score. Significant differences were found between SD and both AD groups for the ACE sub-scores of naming, reading and orientation in time. Discriminant analysis (SD versus AD) led to the formulation of a 'semantic index' (naming plus reading minus scores for serial-7s, orientation in time and drawing). Application of the semantic index to the patient data found values of less than zero to be predictive of SD rather than AD with 88% sensitivity and 90% specificity. Validation analysis in an independent sample of 24 SD and AD patients proved even more favourable. The overall ACE score is known to be a sensitive, and specific, indicator of early neurodegenerative dementia; this study shows that the ACE can also be used to detect SD through application of the semantic index.


GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe?
Glucagon-like peptide 1 receptor (GLP-1R) agonists are increasingly being used as treatment for type 2 diabetes. Since the U.S. Food and Drug Administration published recommendations about the cardiovascular safety of new antidiabetes therapies for treating type 2 diabetes in 2008, the results of two outstanding clinical trials using GLP-1R agonists addressing this issue (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation [LEADER] and Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes [SUSTAIN-6]) have been published. Both studies found beneficial effects in terms of reducing the rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, their results regarding the progression of diabetic retinopathy (DR) were neutral with liraglutide (LEADER) or worse when compared with placebo in the case of semaglutide (SUSTAIN-6). These results are surprising because of the beneficial effects of GLP-1R analogs reported in experimental models of DR. In this Perspective, an overview of the mechanisms by which GLP-1R activation exerts its effects in preventing or arresting experimental DR is given. In addition, we consider the possible reasons for the negative results regarding the progression of DR in the SUSTAIN-6 study, as well as the gaps that still need to be covered to further clarify this important issue in the management of type 2 diabetes.


Exploring the role of miRNAs in early chicken embryonic development and their significance.
In the early stages of embryonic development, a precise and strictly controlled hierarchy of gene expression is essential to ensure proper development of all cell types and organs. To better understand this gene control process, we constructed a small RNA library from 1- to 5-day-old chick embryos, and identified 2,459 miRNAs including 827 existing, 695 known, and 937 novel miRNAs with bioinformatic analysis. There was absolute high expression of a number of miRNAs in each stage, including gga-miR-363-3p (Em1d), gga-miR-26a-5p (Em2d and Em3d), gga-miR-10a-5p (Em4d), and gga-miR-199-5p (Em5d). We evaluated enriched miRNA profiles, identifying VEGF, Insulin, ErbB, MAPK, Hedgehog, TLR and Hippo signaling pathways as primary regulatory mechanisms enabling complex morphogenetic transformations within tight temporal constraints. Pathway analysis revealed miRNAs as pivotal nodes of interaction, coordinating cascades of gene expression critical for cell fate determination, proliferation, migration, and differentiation across germ layers and developing organ systems. Weighted Gene Co-Expression Network Analysis (WGCNA) generated hub miRNAs whose modular connections spanned regulatory networks, including: gga-miR-181a-3p (blue module), coordinating immunegenesis and myogenesis; gga-miR-126-3p (brown module), regulating vasculogenesis and angiogenesis; gga-miR-302c-5p (turquoise module), enabling pluripotency and self-renew; and gga-miR-429-3p (yellow module), modulating neurogenesis and osteogenesis. The findings of this study extend the knowledge of miRNA expression in early embryonic development of chickens, providing insights into the intricate gene control process that helps ensure proper development.


[Anemic syndrome frequency in complicated obstetrical patients].
The prevalence of anemia varies from country to country and there is not a trustworthy record. To determine the frequency of anemia in obstetric patients and the association among healthy pregnancy and aggregate complications. Was carried out as transversal, observational and comparative study. Obstetrical patients entered and responded in the period of a year, were formed a group with normal pregnancy and another with complicated pregnancy, with a total sample of 194 patients. In the statistical analysis was employed Student t test for independent groups, with value if p < 0.05. When was included all patients from both groups of study a general frequency of anemia was found in 22.4%. Hematological stage from group with normal pregnancy was mild anemia in 16.9% and anemia moderated in 4.1% of the cases. The anemia degrees in the group with associated illness and pregnancy were mild anemia in 19.2% and moderated anemia in 4.2%. Not any case was found with severe anemia. The statistical analysis showed difference significant among both groups p < 0.05. The most frequently causes of the obstetrical morbidity were preeclampsia severe (22.6%), type 2 diabetes (13.9%), gestational diabetes (12.2%) and the remainder with other complications that include to the hypertiroidism, rheumatoid arthritis, lupus, asthma and vein deep thrombosis. Frequency of anemia in this study was greater upon informing in the international literature. The obstetrical complication more frequently relates to diverse anemia degrees were the hypertensive stage during pregnancy. The anemia is presented with greater frequency in pregnancy patients with others associated illness.


Time-resolved microscopy with random lasers.
We demonstrate that random lasers provide an outstanding strobe light source for time-resolved microscopy. Utilizing a random laser to illuminate a commercially available microscope enables single exposure, speckle-free time-resolved imaging. Aside from conventional optical transmission microscopy, we also perform time-resolved investigations in phase contrast mode. We apply this method to the monitoring of fs-laser-induced microdot formation in bulk a-SIO(2). Time-resolved investigations show that microdot formation lasts over several microseconds after laser excitation.


Contributions of sustained INa and IKv43 to transmural heterogeneity of early repolarization and arrhythmogenesis in canine left ventricular myocytes.
The roles of sustained components of I(Na) and I(Kv43) in shaping the action potentials (AP) of myocytes isolated from the canine left ventricle (LV) have not been studied in detail. Here we investigate the hypothesis that these two currents can contribute substantially to heterogeneity of early repolarization and arrhythmic risk. Quantitative data from voltage-clamp and expression profiling experiments were used to complete meaningful modifications to an existing "local control" model of canine midmyocardial myocyte excitation-contraction coupling for epicardial and endocardial cells. We include 1) heterogeneous I(Kv43), I(Ks), and I(SERCA) density; 2) modulation of I(Kv43) by Kv channel interacting protein type 2 (KChIP2) channel subunits; 3) a possible Ca(2+)-dependent open-state inactivation of I(Kv43); and 4) a sustained component of the inward Na(+) current, I(NaL). The resulting simulations illustrate ways in which KChIP2- and Ca(2+)-dependent control of I(Kv43) can result in a sustained outward current that can neutralize I(NaL) in a rate- and myocyte subtype-dependent manner. Both these currents appear to play significant roles in modulating AP duration and rate dependence in midmyocardial myocytes. Furthermore, an increased ratio of I(Kv43) to I(NaL) is capable of protecting epicardial myocytes from the early afterdepolarizations resulting from the SCN5A-I1768V mutation-induced increase in I(NaL). Experimentally observed transmural differences in Ca(2+) handling, including greater sarcoplasmic reticulum Ca(2+) content and faster Ca(2+) transient decay rates on the epicardium, were recapitulated in our simulations. By design, these models allow upward integration into organ models or may be used as a basis for further investigations into cellular heterogeneities.


[Portal hypertension in liver cirrhosis].
Portal hypertension is a dramatic complication in liver cirrhosis by efraction of the varices localized more frequently in the esophagus. It has been an actual subject due to physiopathological research (endotelin system, nitric system etc), diagnosis (echoendoscopy, color Doppler), and therapeutically progress. Propranolol, available at a low cost, is efficient and unanimously accepted in the prophylactic treatment of medium and large varices which have never bled as well as in the hemorrhage due to variceal efraction which stopped therapeutically or spontaneously. This drug diminishes the risk of rebleeding. Besides the pharmacological treatment, terlipresine, octreotid, sclerotherapy and bandlegation are used in active hemorrhage due to variceal efraction. If this fails other methods for haemostasis are used: portosystemic transjugular shunt, mechanical tamponade, selective surgery and ideally hepatic transplant. Except for the hepatic transplant, none of the mentioned methods can improve the rate of survival in-patients, which depends on the state of the hepatic failure.


[Morphological changes in brain tissues of rat with local permanent ischemia model under the action of 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate].
The influence of 2-methyl-6-ethyl-3-hydroxypiridine hemisuccinate on the morphological state of rat brain tissue after the occlusion of left middle cerebral artery has been studied. It was found that 6- and 12-day treatment with 2-methyl-6-ethyl-3-hydroxypyridine hemisuccinate at a dose of 100 mg/kg (intraperitoneal) led to regenerative processes in ischemic brain tissue. The latter treatment duration was most effective.


Age as a clinical predictor of relapse after induction therapy in ulcerative colitis.
Whether older patients with ulcerative colitis (UC) have a better clinical course than younger patients is unclear. We compared the clinical characteristics between older and younger age groups in South Korea to elucidate the impact of age on relapse in UC. Patients between 18 and 85 years old who were diagnosed with UC at Seoul National University Bundang Hospital between 1 May 2003 and 31 Oct 2007 were enrolled. It was reviewed their symptoms, endoscopic and pathologic findings, and drugs used in induction treatment. Of the 73 patients with UC who achieved remission after induction treatment, 38 relapsed. The patients aged 18-44 and 45-85 years had similar clinical features, but the relapse rate was significantly higher in the younger group (69.2 vs. 32.4%; p = 0.002). In a multivariable analysis, age 45-85 years old was an independent protective factor against relapse (OR, 0.146; 95% CI, 0.035-0.508; p = 0.003) after adjusting for sex, frequency of diarrhea, hematochezia grade, disease extent, and systemic steroid used in induction treatment. An age of 45 years or older is an independent predictor of less relapse in UC.


Pars plana vitrectomy in the pediatric population: indications and long-term results.
To establish the indications and the long-term results of pars plana vitrectomy (PPV) in the pediatric population. PPV was performed in 60 eyes of 57 children, 45 boys and 12 girls, aged from 6 to 15 years. Twenty-nine eyes (48%) suffered from complicated rhegmatogenous or traction retinal detachment (RD) with advanced proliferative vitreoretinopathy (PVR), 19 eyes (32%) had RD due to an idiopathic or traumatic giant tear (GT), 7 eyes (11%) had an intraocular foreign body (IOFB), and 5 eyes (9%) had hemorrhage or exudation into the vitreous. In 43 eyes (65%) silicone oil implantation (SOI) was indicated, in 39 eyes (91%) a primary SOI, and in 4 eyes (9%) a secondary SOI. The patients were followed up for 6-72 months, mean 42 months. At the end of follow-up, anatomical success with a flat macula was achieved in 77% of the eyes, and functional success with visual acuity of 0.02 and better in 72%. The results were best in IOFB and traction RD after penetrating injury (success in 100% and 91%); the worst results were in RD after regressed retinopathy of prematurity and RD due to idiopathic GT (success in 50% and 54%). After SOI silicone oil was removed in 27 out of 43 eyes (63%), and the retina remained attached in 23 of these eyes (85%). Indications and the long-term results of PPV in children were comparable with those in the adult. By far the most frequent indications were injuries and their complications. In complicated RD, a radical approach with primary SOI and later silicone oil removal proved useful. In children, with their long life expectancy, timely removal of silicone oil is vital for maintaining the function of the eye.


The two forms of karyogamy transcription factor Kar4p are regulated by differential initiation of transcription, translation, and protein turnover.
Kar4p is a transcription factor in Saccharomyces cerevisiae that is required for the expression of karyogamy-specific genes during mating, for the efficient transit from G1 during mitosis, and for essential functions during meiosis. Kar4p exists in two forms: a constitutive slower-migrating form, which predominates during vegetative growth, and a faster-migrating form, which is highly induced by mating pheromone. Transcript mapping of KAR4 revealed that the constitutive mRNA was initiated upstream of two in-frame ATG initiation codons, while the major inducible mRNA originated between them. Thus, the two forms of Kar4p are derived from the translation of alternative transcripts, which possess different AUG initiation codons. Site-directed mutations were constructed to inactivate one or the other of the initiation codons, allowing the expression of the two Kar4p forms separately. At normal levels of expression, the constitutive form of Kar4p did not support wild-type levels of mating. However, the two forms of Kar4p could also be expressed separately from the regulatable GAL1 promoter, and no functional difference was detected when they were expressed at equivalent levels. Pulse-chase experiments showed that the induced form of Kar4p was highly expressed and stable during mating but rapidly turned over in vegetative cells. In contrast, the constitutively expressed longer form showed the same rate of turnover regardless of the growth condition. Furthermore, overexpression of either form of Kar4p in vegetative cells was toxic. Thus, the elaborate regulation of the two forms of Kar4p at the levels of transcription, translation, and protein turnover reflects the requirement for high levels of the protein during mating and for low levels during the subsequent phases of the cell cycle.


Transcription coactivator mediator subunit MED1 is required for the development of fatty liver in the mouse.
Peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that Mediator 1 (MED1; also known as PBP or TRAP220), a key subunit of the Mediator complex, is required for high-fat diet-induced hepatic steatosis as well as PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1(ΔLiv) ) mice, when fed a high-fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1(ΔLiv) mice injected with adenovirus-PPARγ (Ad/PPARγ) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1(fl/fl) ) fed a high-fat diet or injected with Ad/PPARγ developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPARγ-injected mouse livers showed impaired induction in MED1(ΔLiv) mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin, and lipid droplet-associated genes, including caveolin-1, CideA, S3-12, and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1(fl/fl) mouse liver in response to Ad/PPARγ. Re-expression of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1(ΔLiv) mouse liver restored PPARγ-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPARγ overexpression. We conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPARγ-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;).


Vesicular stomatitis New Jersey virus glycoprotein gene sequence and neutralizing epitope stability in an enzootic focus.
Vesicular stomatitis New Jersey (VS NJ) virus is capable of undergoing rapid evolution in nature and therefore has the potential for antigenic variation. We selected an area of Costa Rica where VS NJ virus is enzootic to study whether this virus used the mechanism of antigenic variation to persist in nature. Three sentinel herds and three nonsentinel herds were observed from 1986 to 1988. Eleven VS NJ virus isolates were collected from naturally infected cattle. Remarkably, nine animals that were bled prior to reinfection with VS NJ virus had neutralizing antibody titers up to 1: 102,400 yet virus was isolated from, and disease was observed in, these animals. Sequence analysis of the portion of the glycoprotein gene coding for the neutralizing epitopes demonstrated that all virus isolates were 98-100% similar with no indication of specific genetic variation. The 3' end of the glycoprotein gene also remained stable in that all isolates were again 98-100% similar in nucleotide sequence. Each isolate was neutralized to equivalent titers with monoclonal antibodies directed against four neutralizing epitopes on the glycoprotein. Additionally, preisolation sera from each animal were able to neutralize the virus that caused the subsequent disease. These results provide evidence that antigenic variation is not a mechanism used by VS NJ virus to persist in an enzootic focus of Costa Rica.


Effect of ambulatory versus hospital treatment for gestational diabetes or hyperglycemia on infant mortality rates: a systematic review.
Pregnancies complicated by diabetes are associated with increased neonatal and maternal complications. The most serious maternal complication is the risk of developing type 2 diabetes, 10-12 years after the delivery. For rigorous control over blood glucose, pregnant women are treated through ambulatory management or hospitalization. The aim of this study was to evaluate the effectiveness of ambulatory management versus hospitalization in pregnancies complicated by diabetes or hyperglycemia. Systematic review conducted in a public university hospital. A systematic review of the literature was performed and the main electronic databases were searched. The date of the most recent search was September 4, 2011. Two authors independently selected relevant clinical trials, assessed their methodological quality and extracted data. Only three studies were selected, with small sample sizes. There was no statistically significance different between ambulatory management and hospitalization, regarding mortality in any of the subcategories analyzed: perinatal and neonatal deaths (relative risk [RR] 0.65; 95% confidential interval [CI]: 0.11 to 3.84; P = 0.63); neonatal deaths (RR 0.29; 95% CI: 0.01 to 6.07; P = 0.43); and infant deaths (RR 0.29; 95% CI: 0.01 to 6.07; P = 0.43). This review, based on studies with high or moderate risk of bias, showed that there was no statistically significant difference between ambulatory management and hospital care, regarding reduction of mortality rates in pregnancies complicated by diabetes or hyperglycemia. It also suggested that there is a need for further randomized controlled trials on this issue.


Descriptive and experimental analyses of potential precursors to problem behavior.
We conducted descriptive observations of severe problem behavior for 2 individuals with autism to identify precursors to problem behavior. Several comparative probability analyses were conducted in addition to lag-sequential analyses using the descriptive data. Results of the descriptive analyses showed that the probability of the potential precursor was greater given problem behavior compared to the unconditional probability of the potential precursor. Results of the lag-sequential analyses showed a marked increase in the probability of a potential precursor in the 1-s intervals immediately preceding an instance of problem behavior, and that the probability of problem behavior was highest in the 1-s intervals immediately following an instance of the precursor. We then conducted separate functional analyses of problem behavior and the precursor to identify respective operant functions. Results of the functional analyses showed that both problem behavior and the precursor served the same operant functions. These results replicate prior experimental analyses on the relation between problem behavior and precursors and extend prior research by illustrating a quantitative method to identify precursors to more severe problem behavior. descriptive assessment, functional analysis, lag-sequential analysis, precursors, problem behavior, response-class hierarchies


In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?
In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.


Commissioned article: management of exotic snakebites.
Exotic (foreign or non-native) snakes, including venomous species, are becoming increasingly popular pets in Western countries. Some of them are kept illegally (as defined by the UK Dangerous Wild Animals Act of 1976). There is a large international market for such animals, with contraventions of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). In the UK, several other European countries and the USA the reported numbers of bites by venomous exotic snakes, although small, are increasing but still underestimate the occurrence of these occasionally fatal events because of the victims' reluctance to seek medical care. Victims are predominantly young men who have been drinking alcohol. Bites may be intentionally provoked. In Europe, the species most often involved are cobras, green mambas, American pit vipers particularly rattlesnakes, African adders, vipers and Asian green pit vipers. To illustrate the special problems involved, case histories are presented of bites by exotic species in the UK and of bites abroad, where patients were repatriated for treatment. In view of the relative rarity and diversity of these cases, expert advice must usually be sought. These requests should include information about the species thought to have been responsible and the history and timing of the evolution of envenoming. Sources of advice and antivenom are discussed together with recommendations for appropriate first aid and emergency treatment while this is being awaited. Respiratory and cardiovascular resuscitation may be required and when systemic or severe local envenoming develops, specific (equine or ovine) antivenom is indicated.


Resistance exercise increases intramuscular NF-κb signaling in untrained males.
The NF-κB signaling pathway regulates multiple cellular processes following exercise stress. This study aims to examine the effects of an acute lower-body resistance exercise protocol and subsequent recovery on intramuscular NF-κB signaling. Twenty-eight untrained males were assigned to either a control (CON; n = 11) or exercise group (EX; n = 17) and completed a lower-body resistance exercise protocol consisting of the back squat, leg press, and leg extension exercises. Skeletal muscle microbiopsies were obtained from the vastus lateralis pre-exercise (PRE), 1-hour (1H), 5-hours (5H), and 48-hours (48H) post-resistance exercise. Multiplex signaling assay kits (EMD Millipore, Billerica, MA, USA) were used to quantify the total protein (TNFR1, c-Myc) or phosphorylation status of proteins belonging to the NF-κB signaling pathway (IKKa/b, IkBα, NF-κB) using multiplex protein assay. Repeated measures ANOVA analysis was used to determine the effects of the exercise bout on intramuscular signaling at each time point. Additionally, change scores were analyzed by magnitude based inferences to determine a mechanistic interpretation. Repeated measures ANOVA indicated a trend for a two-way interaction between the EX and CON Group (p = 0.064) for c-Myc post resistance exercise. Magnitude based inference analysis suggest a "Very Likely" increase in total c-Myc from PRE-5H and a "Likely" increase in IkBα phosphorylation from PRE-5H post-resistance exercise. Results indicated that c-Myc transcription factor is elevated following acute intense resistance exercise in untrained males. Future studies should examine the role that post-resistance exercise NF-κβ signaling plays in c-Myc induction, ribosome biogenesis and skeletal muscle regeneration.


Statistical and Proactive Analysis of an Inter-Laboratory Comparison: The Radiocarbon Dating of the Shroud of Turin.
We review the sampling and results of the radiocarbon dating of the archaeological cloth known as the Shroud of Turin, in the light of recent statistical analyses of both published and raw data. The statistical analyses highlight an inter-laboratory heterogeneity of the means and a monotone spatial variation of the ages of subsamples that suggest the presence of contaminants unevenly removed by the cleaning pretreatments. We consider the significance and overall impact of the statistical analyses on assessing the reliability of the dating results and the design of correct sampling. These analyses suggest that the 1988 radiocarbon dating does not match the current accuracy requirements. Should this be the case, it would be interesting to know the accurate age of the Shroud of Turin. Taking into account the whole body of scientific data, we discuss whether it makes sense to date the Shroud again.


Lower Extremity Joint Angle Tracking with Wireless Ultrasonic Sensors during a Squat Exercise.
This paper presents an unrestrained measurement system based on a wearable wireless ultrasonic sensor network to track the lower extremity joint and trunk kinematics during a squat exercise with only one ultrasonic sensor attached to the trunk. The system consists of an ultrasound transmitter (mobile) and multiple receivers (anchors) whose positions are known. The proposed system measures the horizontal and vertical displacement, together with known joint constraints, to estimate joint flexion/extension angles using an inverse kinematic model based on the damped least-squares technique. The performance of the proposed ultrasonic measurement system was validated against a camera-based tracking system on eight healthy subjects performing a planar squat exercise. Joint angles estimated from the ultrasonic system showed a root mean square error (RMSE) of 2.85° ± 0.57° with the reference system. Statistical analysis indicated great agreements between these two systems with a Pearson's correlation coefficient (PCC) value larger than 0.99 for all joint angles' estimation. These results show that the proposed ultrasonic measurement system is useful for applications, such as rehabilitation and sports.


Tamsulosin alters levofloxacin pharmacokinetics in prostates derived from rats with acute bacterial prostatitis.
The combination of levofloxacin and α1 adrenergic antagonist treatment is the current preferred choice for both bacterial and non-bacterial prostatitis. The aim of this study is to explore the influence of α1 adrenergic antagonists on the pharmacokinetics of levofloxacin using rat models with acute bacterial prostatitis (ABP) induced by direct injection with Escherichia coli (ATCC25922). A total of 96 model rats were randomly assigned into two groups: the experimental group (treated with both tamsulosin and levofloxacin, n=48) and the control group (treated with levofloxacin and solvents, n=48). Six rats from each group were euthanized to collect blood, liver, kidney and prostate samples at the time points of 0.125, 0.25, 0.5, 1, 2, 4, 8 and 12 h after drug administration. The levofloxacin concentrations were detected by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated using the 3p97 software program. There were no obvious differences (P>0.05) between the experimental and control groups in the major pharmacokinetic parameters of levofloxacin, including the halftime (t1/2), time to peak (tpeak), clearance rate (CL), maximum concentration (Cmax) and area under the curve (AUC0∼12), in the plasma or in the hepatic and kidney tissues of the model rats. However, in the prostatic tissues, tamsulosin increased the Cmax, prolonged the t1/2 and decreased the CL of levofloxacin (P<0.05). These results indicate that tamsulosin may enhance the effect of levofloxacin in the treatment of bacterial prostatitis without changing the drug concentration in the liver and kidney.


Are Urban Vertebrates City Specialists, Artificial Habitat Exploiters, or Environmental Generalists?
Although urbanization is a major threat to biodiversity, some species are able to thrive in cities. This might be because they have specific adaptations to urban conditions, because they are able to cope with artificial habitats in general or because they are generalists that can live in a wide range of conditions. We use the latest version of the IUCN database to distinguish these possibilities in 25,985 species of the four classes of terrestrial vertebrates with the help of phylogenetically controlled methods. We first compare species occurrence in cities with that of the five other artificial habitats recognized by the IUCN and use principal components analyses to ask which of these most resembles cities. We then test whether urban species have a wider habitat breadth than species occurring in other, non-urban, artificial habitats, as well as species that occur only in natural habitats. Our results suggest that the proportion of terrestrial vertebrates that occur in urban environments is small and that, among the species that do occur in cities, the great majority also occur in other artificial habitats. Our data also show that the presence of terrestrial vertebrates in urban habitats is skewed in favor of habitat generalists. In birds and mammals, species occurrence in urban areas is most similar to that of rural gardens, while in reptiles and amphibians, urban areas most resemble pasture and arable land. Our study suggests that cities are likely not unique, as is often thought, and may resemble other types of artificial environments, which urban exploiters can adapt to because of their wide habitat breadth.


Acute effect of glucocorticoid treatment on serum osteocalcin levels in asthmatic children.
The serum levels of osteocalcin (OC), a sensitive and specific biochemical marker of bone formation, were measured in 36 asthmatic children before and after intravenous administration of glucocorticoid (GC), methylprednisolone (1 mg/kg/6 h). A statistically significant (p < 0.005) decrease in OC level (13.5-2.7 microg/L) after the completion of 1-day treatment. In patients who received 2-day treatment, the OC levels further declined and reached about 20% of the pretreatment levels. Blood samples collected from patients who received 3-day treatment showed serum OC had declined to an even lower level after the completion of therapy (11.5-1.8 microg/L). An inverse relationship was found between the OC concentration and the duration of GC therapy. GC therapy induced a minor, significant decrease of serum alkaline phosphatase level but did not influence serum calcium level. A tendency toward decrease of serum phosphate level was also noted during GC treatment. An acute effect of GC therapy on the suppression of osteoblasts was biochemically revealed by the finding of reduced serum OC levels. The results suggest that early change in serum OC may be a useful indicator for patients at high risk of bone loss.


Photomanipulation of the anchoring strength of a photochromic nematic liquid crystal.
The behavior of the Fréedericksz threshold voltage of a planarly oriented sample filled with liquid crystalline azobenzene material possessing a nematic phase is investigated under UV illumination. It is found that the anchoring strength strongly decreases with the UV-exposure time due to the photoisomerization process that takes place in the sample. The changes in the anchoring strength are due to a selective adsorption of cis isomers at the surface. We show that the experimental data can be explained by a model that takes into account the changes in the molecular shape and in the net molecular dipole moment due to the cis-trans isomerization. We obtain a good agreement between the predictions of the model and the experimental data.


von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina.
In early neonates, the fetal circulatory system undergoes dramatic transition to the adult circulatory system. Normally, embryonic connecting vessels, such as the ductus arteriosus and the foramen ovale, close and regress. In the neonatal retina, hyaloid vessels maintaining blood flow in the embryonic retina regress, and retinal vessels take over to form the adult-type circulatory system. This process is regulated by a programmed cell death switch mediated by macrophages via Wnt and angiopoietin 2 pathways. In this study, we seek other mechanisms that regulate this process, and focus on the dramatic change in oxygen environment at the point of birth. The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor alphas (HIF-alphas) under normoxic, but not hypoxic, conditions. To examine the role of oxygen-sensing mechanisms in retinal circulatory system transition, we generated retina-specific conditional-knockout mice for VHL (Vhl(alpha)(-CreKO) mice). These mice exhibit arrested transition from the fetal to the adult circulatory system, persistence of hyaloid vessels and poorly formed retinal vessels. These defects are suppressed by intraocular injection of FLT1-Fc protein [a vascular endothelial growth factor (VEGF) receptor-1 (FLT1)/Fc chimeric protein that can bind VEGF and inhibit its activity], or by inactivating the HIF-1alpha gene. Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina.


Behavior patterns of socially rejected and neglected preadolescents: the roles of social approach and aggression.
Sociometric nominations were used to select groups of popular, average, rejected, and neglected third- and fifth-grade children. In two studies, the peer interactive behaviors of these children were naturalistically observed in their classrooms and on the playground. In contrast to popular children, rejected children displayed fewer task-appropriate behaviors and more task-inappropriate and aggressive behaviors. Whereas rejected children prosocially approached peers as frequently as did popular children, peer responses to the approaches of rejected children were more likely to be negative. Neglected children, on the other hand, displayed relatively few task-inappropriate and aggressive behaviors, and socially approached peers infrequently. Their approaches also met with frequent rebuff by peers. The findings were discussed in terms of the behavioral bases of sociometric status. Suggestions were made for clinical researchers interested in behavioral change with rejected and neglected children.


Understanding the host genetics of chronic hepatitis B and C.
The outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are heterogeneous, ranging from an asymptomatic self-limiting infection to cirrhosis and hepatocellular carcinoma. Several viral environmental and demographic variables have been identified as determinants of disease outcome, but these fail to explain a large proportion of the variability. Evidence from twin studies suggests that the host genetic background is an important contributor to disease outcome. Identification of genes that influence the outcome of infection has been attempted using a wide spectrum of approaches including candidate gene disease association studies, genome-wide scanning in affected sibling pairs and most recently genome-wide association studies. We summarize the main findings from a large number of studies in this review. Many studies have focused on the MHC loci from which several reproducible disease associations have been identified. More recently, genome-wide association studies have identified an important locus within the IL-28 - Il-29 region on chromosome 29, which appears to be a major determinant of the treatment response in patients infected with HCV and also a determinant of spontaneous resolution of infection. Translation of the genetic architecture of chronic viral hepatitis into therapeutic opportunities has been slow to proceed. One clinical trial and one drug development program have been based on genetic discoveries. The use of IL-28B genotyping to predict the response to pegylated interferon and ribavirin may also find its way into clinical practice. Indeed, stratification of clinical trial populations based on IL-28B genotype is already considered mandatory.


Population Pharmacokinetic Modeling and Probability of Target Attainment Analyses in Asian Patients With Community-Acquired Pneumonia Treated With Ceftaroline Fosamil.
Efficacy of ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, was demonstrated in a phase 3 study of hospitalized Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV community-acquired pneumonia (NCT01371838). The objectives of the current analysis were to expand an existing ceftaroline and ceftaroline fosamil population pharmacokinetic (PK) model with data from this phase 3 study and a phase 1 study (NCT01458743) assessing ceftaroline PK in healthy Chinese volunteers and to evaluate the probability of PK/pharmacodynamic (PK/PD) target attainment (PTA) in Asian patients with community-acquired pneumonia (CAP) treated with ceftaroline fosamil. The ceftaroline plasma concentration-time course was simulated for 5000 Asian patients with CAP for different renal function subgroups using the final model. PTA was calculated for Streptococcus pneumoniae, Staphylococcus aureus, and non-extended-spectrum β-lactamase-producing Enterobacteriaceae. PTA was also evaluated for ceftaroline MIC90 values of isolates collected from Asia-Pacific surveillance studies (2012-2014) and for EUCAST and FDA/CLSI ceftaroline susceptibility break points. The final model reasonably described the ceftaroline PK. Race was not found to be a significant covariate impacting ceftaroline PK, suggesting similar ceftaroline PK in Asian and Western populations when corrected for body weight. High PTAs (90%-100%) were predicted for Asian patients with CAP treated with ceftaroline fosamil, covering MIC90 values of target CAP pathogens from the region. Similarly, >90% PTAs were predicted at EUCAST and FDA/CLSI clinical break points for these pathogens. These results support the use of the ceftaroline fosamil dosing regimens approved in Europe and the United States in Asian patients with PORT III-IV CAP.


H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome.
Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68+ /H-ferritin+ and CD68+ /L-ferritin+ ; and (iii) interleukin (IL)-1β, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these results with clinical data. H-ferritin, IL-1β, TNF and IFN-γ were increased significantly in MAS. Furthermore, an increased number of CD68+ /H-ferritin+ cells and an infiltrate of cells co-expressing H-ferritin and IL-12, suggesting an infiltrate of M1 macrophages, were observed. H-ferritin levels and CD68+ /H-ferritin+ cells were correlated with haematological involvement of the disease, serum ferritin and C-reactive protein. L-ferritin and CD68+ /L-ferritin+ cells did not correlate with these parameters. In conclusion, during MAS, H-ferritin, CD68+ /H-ferritin+ cells and proinflammatory cytokines were increased significantly in the BM inflammatory infiltrate, pointing out a possible vicious pathogenic loop. To date, H-ferritin and CD68+ /H-ferritin+ were associated significantly with haematological involvement of the disease, suggesting biomarkers assessing severity of clinical picture.


Preparation of reusable hydrogel spheres based on sodium alginate/Fe3O4 modified with carboxymethyl Huangshui polysaccharide and the efficient adsorption performance for methylene blue.
This study successfully constructed a novel multifunctional bio-adsorbent using sodium alginate (SA), ferroferric oxide (FFO), and carboxymethyl Huangshui polysaccharide (CMHSP) with rapid separation, pH sensitivity, efficient adsorption, and reusability for enhancing the removal of methylene blue (MB) in wastewater. FTIR, XRD, SEM, and VSM results indicated CMHSP improved the porosity of the hydrogel spheres, thus significantly enhancing the MB adsorption capacity with the rate-limiting controlled by chemical adsorption, intraparticle diffusion, and film diffusion. The maximum adsorption capacity obtained from Langmuir model of SA-FFO-CMHSP (186.57 mg/g) was obviously higher than that of SA-FFO (178.82 mg/g). Thermodynamic results showed that the MB adsorption process was endothermic, spontaneous, and favorable, and physical adsorption was dominant. Remarkably, MB adsorption maintained 87% ∼ 95% of the initial after four adsorption-desorption cycles, and proper carboxymethylation was conducive to MB adsorption over a broader range pH. These findings provided reference for designing new efficient bio-adsorbents and the recyclable utilization of Huangshui by-products, which was of great value.


The 'placement' of people with profound impairments across the lifespan: re-thinking age criteria.
Advances in lifesaving technologies and treatments make it possible for children with profound physical and cognitive impairments to survive into adulthood. Questions regarding how and where they should live are discussed rarely and, when they are, primarily focus on safety and/or containing costs. Since models of long-term care provision are age-based, children who reside in institutions are 'discharged' to adult facilities when they reach an arbitrary age. Such transfers may not be in the best interests of these young people or their families. Our aim in this debate is to highlight why age is a problematic criterion for placement decisions, with the goal of stimulating further research and inquiry. Transfers from pediatric to adult institutions are driven primarily by funding arrangements and underpinned by stage-based theories of human development. Arguments supporting such transfers point to the value of communal living with same age peers, and engagement in age-appropriate activities. These goals are questionable for individuals who are minimally interactive and/or where equally worthy interactions are feasible in intergenerational settings. Instead their accommodation needs might more closely align with palliative care principles of supporting individuals and families to enjoy what they bring to each other's lives and minimize suffering. Innovative models of 'vertical care' and 'lifetime homes', which enable continuous flexible services across the lifespan, are discussed as examples of alternative approaches requiring further debate and research. Entrenched funding and service models that require the transfer of profoundly impaired young people from pediatric to adult facilities need to be re-examined with considerations of best interests, needs, and preferences of individuals and their families. Questions of what constitutes a 'good life' for these individuals are tenacious and require further thought and research. Nevertheless, they need to be regarded as citizens of our human community deserving of a good life in whatever form that may take, in settings that enable them to flourish.


Children's Out-of-School Independently Mobile Trips, Active Travel, and Physical Activity: A Cross-Sectional Examination from the Kids in the City Study.
The study aim was to determine the association between children's objectively assessed moderate-to-vigorous physical activity (MVPA) and active trips (AT) and independently mobile trips (IM) during out-of-school hours. Children aged 9 to 13 years (n = 254) were recruited from 9 schools in Auckland, New Zealand between 2011 and 2012. Children completed travel diaries and wore accelerometers for 7 days. Parents provided demographic information. Geographic information systems-derived distance to school was calculated. Accelerometer data were extracted for out of school hours only. Percentage of time spent in MVPA (%MVPA), AT, and IM were calculated. Generalized estimating equations were used to determine the relationship between daily %MVPA and AT and between daily %MVPA and IM, accounting for age, sex, ethnicity, distance to school, day of the week, and numeric day of data collection. A significant positive relationship was observed between %MVPA and both AT and IM. For every unit increase in the daily percentage of trips made that were AT or IM, we found an average increase of 1.28% (95% CI 0.87%, 1.70%) and 1.15% (95% CI 0.71%, 1.59%) time in MVPA, respectively. Children's AT and IM are associated with increased MVPA during out-of-school hours.


Tumor-promoting phorbol esters induce angiogenesis in vivo.
It has been hypothesized that tumor growth is dependent on the concomitant growth of its vascular supply, and thus agents that stimulate angiogenesis may help support tumor growth. Phorbol esters are potent tumor promoters that induce a variety of biochemical effects in cells, including activation of protein kinase C. The specific mechanisms responsible for tumor promotion by phorbol esters are unknown. The objective of this study was to determine whether the tumor-promoting phorbol esters can induce vascular growth. Phorbol esters were tested for their ability to stimulate angiogenesis in vivo using the chick chorioallantoic membrane and rabbit cornea assays. The active tumor promoters 12-O-tetradecanoyl phorbol-13-acetate and phorbol 12,13-didecanoate, which activate protein kinase C, were found to stimulate angiogenesis in a dose-dependent manner. In contrast, 4 alpha-phorbol 12,13-didecanoate, which is inactive as a tumor promoter and does not activate protein kinase C, did not stimulate angiogenesis. Phorbol esters may be indirect angiogenic factors, since no mitogenic effect on bovine capillary endothelial cells in culture could be detected. The results demonstrate that the tumor-promoting activity of phorbol esters may, in part, be secondary to stimulation of neovascularization to support tumor growth and suggest a role for the activation of protein kinase C in this process.


Structure-activity relationship analysis of N-benzoylpyrazoles for elastase inhibitory activity: a simplified approach using atom pair descriptors.
Previously, we utilized high throughput screening of a chemical diversity library to identify potent inhibitors of human neutrophil elastase and found that many of these compounds had N-benzoylpyrazole core structures. We also found individual ring substituents had significant impact on elastase inhibitory activity and compound stability. In the present study, we utilized computational structure-activity relationship (SAR) analysis of a series of 53 N-benzoylpyrazole derivatives to further optimize these lead molecules. We present an improved approach to SAR methodology based on atom pair descriptors in combination with 2-dimensional (2D) molecular descriptors. This approach utilizes the rich representation of chemical structure and leads to SAR analysis that is both accurate and intuitively easy to understand. A sequence of ANOVA, linear discriminant, and binary classification tree analyses of the molecular descriptors led to the derivation of SAR rule-based algorithms. These rules revealed that the main factors influencing elastase inhibitory activity of N-benzoylpyrazole molecules were the presence of methyl groups in the pyrazole moiety and ortho-substituents in the benzoyl radical. Furthermore, our data showed that physicochemical characteristics (energy of frontier molecular orbitals, molar refraction, lipophilicity) were not necessary for achieving good SAR, as comparable quality of SAR classification was obtained with atom pairs and 2D descriptors only. This simplified SAR approach may be useful to qualitative SAR recognition problems in a variety of data sets.


Caesarean section in Christchurch.
Base hospital caesarean section rates in Christchurch have risen from 4.1% in 1967 to 14.1% in 1982. However, the Christchurch district caesarean section rate for 1982 was only 9.6%. Analysis of the indications for caesarean section according to the year showed that most indications have increased in frequency and that between 1977 and 1982 this increase was highly significant for failure to progress and fetal distress. Analysis of the indications for caesarean section according to the type of antenatal booking revealed that in 1982 private patients underwent caesarean section more frequently than clinic patients and that they were more likely to have the caesarean section for failure to progress or fetal distress. Emergency transfer patients had an even higher primary caesarean section rate for most indications.


Atmospheric distribution of polychlorinated dibenzo-p-dioxins, dibenzofurans and dioxin-like polychlorinated biphenyls around a steel plant area, northeast China.
Air monitoring of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (PCBs) was carried out in June 2008 and January 2009 to investigate the concentrations, profiles and estimating potential inhalation risks to the local residents around a steel plant area in northeast China. The air concentrations and WHO-TEQs of PCDD/Fs ranged 94-4944fgm(-3) (average 1352fgm(-3)) and 3-247fgm(-3) (average 81fgm(-3)), respectively. The WHO-TEQ concentrations of dioxin-like PCBs ranged 1-18fgm(-3) (average 5fgm(-3)), contributing to 3.6-26% of the total TEQ. Higher PCDD/F concentrations were observed in the winter, whereas higher dioxin-like PCB concentrations were found in the summer. The seasonal trend can be related to the significant correlation between the concentrations of dioxins and the reciprocal of temperature (positive for PCDD/Fs, P<0.01; negative for dioxin-like PCBs, P=0.05). A significant positive correlation (P<0.0001) was found between the concentration of total suspended particulate (TSP) and PCDD/F concentrations, but not for PCB congeners. Although the steel plant sites showed higher dioxin levels than the residential and background areas, the PCDD/F levels in the atmosphere of the steel plant area was at a relatively low level. The results from this study provides further aid in evaluating the impact of steel plants as PCDD/Fs emission sources to the ambient air in China.


Exosome-Laden Scaffolds for Treatment of Post-Traumatic Cartilage Injury and Osteoarthritis of the Knee: A Systematic Review.
Mesenchymal stem cell (MSC)-based exosomes have garnered attention as a viable therapeutic for post-traumatic cartilage injury and osteoarthritis of the knee; however, efforts for application have been limited due to issues with variable dosing and rapid clearance in vivo. Scaffolds laden with MSC-based exosomes have recently been investigated as a solution to these issues. Here, we review in vivo studies and highlight key strengths and potential clinical uses of exosome-scaffold therapeutics for treatment of post-traumatic cartilage injury and osteoarthritis. In vivo animal studies were gathered using keywords related to the topic, revealing 466 studies after removal of duplicate papers. Inclusion and exclusion criteria were applied for abstract screening and full-text review. Thirteen relevant studies were identified for analysis and extraction. Three predominant scaffold subtypes were identified: hydrogels, acellular extracellular matrices, and hyaluronic acid. Each scaffold-exosome design showcased unique properties with relation to gross findings, tissue histology, biomechanics, and gene expression. All designs demonstrated a reduction in inflammation and induction of tissue regeneration. The results of our review show that current exosome-scaffold therapeutics demonstrate the capability to halt and even reverse the course of post-traumatic cartilage injury and osteoarthritis. While this treatment modality shows incredible promise, future research should aim to characterize long-term biocompatibility and optimize scaffold designs for human treatment.


Corona ions from overhead transmission voltage powerlines: effect on direct current electric field and ambient particle concentration levels.
Along with their essential role in electricity transmission and distribution, some powerlines also generate large concentrations of corona ions. This study aimed at the comprehensive investigation of corona ions, vertical direct current electric field (dc e-field), ambient aerosol particle charge, and particle number concentration levels in the proximity of some high/subtransmission voltage powerlines. The influence of meteorology on the instantaneous value of these parameters and the possible existence of links or associations between the parameters measured were also statistically investigated. The presence of positive and negative polarities of corona ions was associated with variation in the mean vertical dc e-field, ambient ion, and particle charge concentration level. Though these variations increased with wind speed, their values also decreased with distance from the powerlines. Predominately positive polarities of ions were recorded up to a distance of 150 m (with the maximum values recorded 50 m downwind of the powerlines). At 200 m from the source, negative ions predominated. Particle number concentration levels, however, remained relatively constant (10(3) particle cm(-3)), irrespective of the sampling site and distance from the powerlines. Meteorological factors of temperature, humidity, and wind direction showed no influence on the electrical parameters measured. The study also discovered that e-field measurements were not necessarily a true representation of the ground-level ambient ion/particle charge concentrations.


Relationship between Hay Fever and Mineral Concentration in the Hair, Lifestyle or Aging.
It is important to ingest just proportions of minerals to prevent disease, but these minerals are also secreted into the hair. Meanwhile, the number of hay fever patients in Japan is increasing, causing an increase in national medical expenses. In this study, we investigated the relationship between hay fever and mineral concentrations in hair to obtain findings on the risk of developing pollen allergies. A questionnaire survey was conducted for 275 men and 977 women on their lifestyle habits and ten kinds of mineral concentrations present in their hair were measured with subsequent analysis using nominal logistic regression analysis. The results indicated that half the patients in each age group had hay fever, with no significant difference between hay fever and aging, exercise habits, sleep and dietary rhythms. On the other hand, there was a significant difference between hay fever and mineral concentrations in the hair, and in men with hay fever, iron (odds ratio: 0.55, p<0.05) was low, while in women calcium (odds ratio: 0.67, p<0.05), chromium (odds ratio: 0.46, p<0.001), cadmium (odds ratio: 0.68, p<0.01) were low and selenium (odds ratio: 1.78, p<0.01) was high. These results, suggest that measurements mineral concentrations in hair are indicators of hay fever risk.


Statistical analysis of salivary pH changes after the intake of black tea and yerba maté supplemented with sweeteners.
Many studies have demonstrated the effect of various beverages on hard tissues of the mouth. Sugar consumption has also been avoided because it is associated with caries activity, and artificial sweetener research has been promoted. In this paper, data about the buffer capacity of black tea and yerba mate supplemented with sugar or one of two artificial sweeteners (Barny diet and NutraSweet) were examined. Salivary pH variations after the ingestion of both infusions were statistically analysed. A factorial design of four variables (Infusion, Sweetener, Concentration and Time) and their effects were considered independently and combined. The addition of sucrose lowered the pH of the infusions while black tea showed a greater buffer capacity than yerba mate. Significant differences (p < 0.0001) were obtained when salivary pH values were compared between infusions supplemented with sugar or artificial sweeteners. When a factorial design was used to examine differences between Barny diet and NutraSweet, no significant two- or three-way interactions could be observed. This statistical analysis showed a small significant variation in salivary pH after the ingestion of black tea or yerba mate with sugar but not with artificial sweeteners at the recommended concentrations.


Evaluating the effect of emergency department crowding on triage destination.
Emergency Department (ED) crowding has been studied for the last 20 years, yet many questions remain about its impact on patient care. In this study, we aimed to determine if ED crowding influenced patient triage destination and intensity of investigation, as well as rates of unscheduled returns to the ED. We focused on patients presenting with chest pain or shortness of breath, triaged as high acuity, and who were subsequently discharged home. This pilot study was a health records review of 500 patients presenting to two urban tertiary care EDs with chest pain or shortness of breath, triaged as high acuity and subsequently discharged home. Data extracted included triage time, date, treatment area, time to physician initial assessment, investigations ordered, disposition, and return ED visits within 14 days. We defined ED crowding as ED occupancy greater than 1.5. Data were analyzed using descriptive statistics and the χ(2) and Fisher exact tests. Over half of the patients, 260/500 (52.0%) presented during conditions of ED crowding. More patients were triaged to the non-monitored area of the ED during ED crowding (65/260 (25.0%) vs. 39/240 (16.3%) when not crowded, P = 0.02). During ED crowding, mean time to physician initial assessment was 132.0 minutes in the non-monitored area vs. 99.1 minutes in the monitored area, P <0.0001. When the ED was not crowded, mean time to physician initial assessment was 122.3 minutes in the non-monitored area vs. 67 minutes in the monitored area, P = 0.0003. Patients did not return to the ED more often when triaged during ED crowding: 24/260 (9.3%) vs. 29/240 (12.1%) when ED was not crowded (P = 0.31). Overall, when triaged to the non-monitored area of the ED, 44/396 (11.1%) patients returned, whereas in the monitored area 9/104 (8.7%) patients returned, P = 0.46. ED crowding conditions appeared to influence triage destination in our ED leading to longer wait times for high acuity patients. This did not appear to lead to higher rates of return ED visits amongst discharged patients in this cohort. Further research is needed to determine whether these delays lead to adverse patient outcomes.


CD4-Positive T-Cell Large Granular Lymphocytosis Mimicking Sezary Syndrome in a Patient With Mycosis Fungoides.
A white woman aged 65 years presented with a macular, nonscaly, nonpruritic, erythematous lesion on her right breast. Test results revealed histological features similar to lichenoid dermatitis and early-phase primary cutaneous T-cell lymphoma with a subtype of mycosis fungoides (MF). Despite topical therapy with steroids, her skin disease continued to progress, so she underwent polymerase chain reaction and gene mutation testing. Two missense mutations were detected. The overall findings supported a diagnosis of co-occurring, CD4-positive large granular lymphocytosis and stage IA MF. The patient continued to receive topical steroids and maintenance phototherapy, and her skin lesions completely resolved after 14 weeks of therapy. Approximately 5 years after her initial presentation, she was free of symptoms, cytopenia, and no skin lesions were present. CD4-positive, large granular lymphocytosis was persistent. This patient case - to our knowledge, the first of its kind - posed dilemmas of a diagnostic and therapeutic nature. Correctly staging the lymphoma helped to aid the diagnosis and can help prevent patients similar to the one in this case from receiving unnecessary therapy.


Obesity and pancreatitis.
The obesity pandemic poses a unique set of problems for acute pancreatitis - both by increasing acute pancreatitis incidence, and worsening acute pancreatitis severity. This review explores these associations, underlying mechanisms, and potential therapies. We review how the obesity associated increase in gallstones, surgical, and endoscopic interventions for obesity management, diabetes, and related medications such as incretin-based therapies and hypertriglyceridemia may increase the incidence of acute pancreatitis. The mechanism of how obesity may increase acute pancreatitis severity are discussed with a focus on cytokines, adipokines, damage-associated molecular patterns and unsaturated fatty acid-mediated lipotoxicity. The role of obesity in exacerbating pancreatic necrosis is discussed; focusing on obesity-associated pancreatic steatosis. We also discuss how peripancreatic fat necrosis worsens organ failure independent of pancreatic necrosis. Last, we discuss emerging therapies including choice of intravenous fluids and the use of lipase inhibitors which have shown promise during severe acute pancreatitis. We discuss how obesity may contribute to increasing acute pancreatitis incidence, the role of lipolytic unsaturated fatty acid release in worsening acute pancreatitis, and potential approaches, including appropriate fluid management and lipase inhibition in improving acute pancreatitis outcomes.


Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts.
In this age of molecularly targeted drug discovery, robust techniques are required to measure pharmacodynamic (PD) responses in tumors so that drug exposures can be associated with their effects on molecular biomarkers and efficacy. Our aim was to develop a rapid screen to monitor PD responses within xenografted human tumors as an important step towards a clinically applicable technology. Currently there are various methods available to measure PD end points, including immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction, gene expression profiling, and western blotting. These may require relatively large samples of tumor, surrogate tissue, or peripheral blood lymphocytes with subsequent analyses taking several days. The phosphoinositide 3-kinase (PI3-kinase) pathway is frequently deregulated in cancer and is also important in diabetes and autoimmune conditions. In this paper, optimization of the Meso Scale Discovery (MSD) (Gaithersburg, MD) platform to quantify changes in phospho-AKT and phospho-glycogen synthase kinase-3beta in response to a PI3-kinase inhibitor, LY294002, is described, initially in vitro and then within xenografted solid tumors. This method is highly practical with high throughput since large number of samples can be run simultaneously in 96-well format. The assays are robust (coefficient of variation for phospho-AKT 13.4%) and offer significant advantages (in terms of speed and quantitation) over western blots. This optimized procedure can be used for both in vitro and in vivo analysis, unlike an established fixed-cell ELISA with a time-resolved fluorescent end point.


An Innovative Needle-free Injection System: Comparison to 1 ml Standard Subcutaneous Injection.
A needle-free delivery system may lead to improved satisfaction and compliance, as well as reduced anxiety among patients requiring frequent or ongoing injections. This report describes a first-in-man assessment comparing Portal Instruments' innovative needle-free injection system with subcutaneous injections using a 27G needle. Forty healthy volunteer participants each received a total of four injections of 1.0 mL sterile saline solution, two with a standard subcutaneous injection using a 27G needle, and two using the Portal injection system. Perception of pain was measured using a 100-mm visual analog scale (VAS). Injection site reactions were assessed at 2 min and at 20-30 min after each injection. Follow-up contact was made 24-48 h after the injections. Subject preference regarding injection type was also assessed. VAS pain scores at Portal injection sites met the criteria to be considered non-inferior to the pain reported at 27G needle injection sites (i.e., upper 95% confidence bound less than +5 mm). Based on a mixed effects model, at time 0, accounting for potential confounding variables, the adjusted difference in VAS scores indicated that Portal injections were 6.5 mm lower than the 27G needle injections (95% CI -10.5, -2.5). No clinically important adverse events were noted. Portal injections were preferred by 24 (60%) of the subjects (P = 0.0015). As an early step in the development of this new needle-free delivery system, the current study has shown that a 1.0-mL saline injection can be given with less pain reported than a standard subcutaneous injection using a 27G needle.


Effect of geometrical structure on the biodegradation of a three-dimensionally perforated porous apatite/collagen composite bone cell scaffold.
A Biodegradable artificial bone with inter-connective pores was prepared using a self-setting apatite/collagen composite cement as a cell scaffold for bone regenerative medicine, and investigated as to biocompatibility by X-ray computed tomography (CT) after its implantation into rats. Blocks (APN, APC and ACC) of apatite cement, apatite cement with continuous holes, and apatite/collagen composite cement with continuous holes were prepared. The APC and ACC blocks had 16 (8x2) interconnecting holes 500 microm in diameter. After the APN, APC, and ACC blocks were implanted in the back of the rats, X-ray CT images were measured every week. Before and after implantation, powder X-ray diffraction profiles of APN, APC and ACC showed diffraction patterns of hydroxyapatite with low crystallinity. Changes in the volume, inorganic content and density of the blocks in the rats were evaluated based on X-ray CT images. The volume and inorganic content of ACC decreased continuously at a constant rate. In contrast, the volume and inorganic content of APN and APC didn't show major changes. After implantation, the absorption of X-rays by ACC decreased with time. This suggested that the block was bioabsorbed significantly with time. In contrast, the absorption of APC and APN did not decrease, indicating that the blocks were not bioabsorbed.


Dental management of the patient with Alzheimer's disease.
This paper summarizes factors to be considered in the dental management of the patient who presents with Alzheimer's disease. The information contained in this article will expand the understanding of the etiology, suspected pathophysiology and the clinical features of patients with Alzheimer's who may present for oral rehabilitation. The objective is to better prepare the dental professional in order that he/she may provide effective treatment planning for these patients.


A comparison of microLC/electrospray ionization-MS and GC/MS for the measurement of stable isotope enrichment from a [2H2]-glucose metabolic probe in T-cell genomic DNA.
Measurement of the proliferation of lymphocytes and other high-turnover cell populations in vivo can be accomplished through the incorporation of an isotopically labeled DNA precursor into actively dividing cells and the subsequent determination of the isotope enrichment in the isolated genomic DNA from selected cell populations. Two published gas chromatography/mass spectrometry (GC/MS) methods were successfully modified by our laboratory whereby a postinjection methylation reaction, rather than silylation or acetylation, was used to form a volatile derivative of deoxyadenosine (dA). We also developed a second robust microcapillary liquid chromatography-electrospray ionization (microLC-ESI)/MS method that is faster and more sensitive than the GC/MS method and does not require sample derivatization. Following administration of [6,6-(2)H(2)]-glucose to human immunodeficiency virus-infected patients, peripheral blood was drawn; cells were obtained by lymphapheresis and fractionated. DNA was isolated from the desired cell subtypes and enzymatically hydrolyzed to the free deoxyribonucleosides. The digest was analyzed using both capillary GC/MS and microLC/ESI-MS to measure the levels of the dA and [(2)H(2)]-dA or their reaction products. Sample enrichments were calculated by comparison to standard curves prepared from dA and [(2)H(2)]-dA. The microLC/ESI-MS method required fewer cells, less sample preparation, shorter analysis times, and a single calibration curve. Overall, the microLC/ESI-MS method is superior to the GC/MS method in terms of precision and accuracy, while providing a 4-fold increase in sensitivity (from 20 pmol at 0.2% [(2)H(2)]-dA enrichment to 5 pmol at 0.1% [(2)H(2)]-dA enrichment).


Hemoglobin-Improved Protection in Cultured Cerebral Cortical Astroglial Cells: Inhibition of Oxidative Stress and Caspase Activation.
Oxidative stress plays a major role in triggering astroglial cell death in diverse neuropathological conditions such as ischemia and neurodegenerative diseases. Numerous studies indicate that hemoglobin (Hb) is expressed in both resting and reactive glia cells, but nothing is known regarding a possible role of Hb on astroglial cell survival. Thus, the purpose of the present study was to investigate the potential glioprotective effect of Hb on hydrogen peroxide (H2O2)-induced oxidative stress and apoptosis in cultured rat astrocytes. Our study demonstrates that administration of graded concentrations of Hb (10-12 to 10-6 M) to H2O2-treated astrocytes reduces cell death in a concentration-dependent manner. H2O2 treatment induces the accumulation of reactive oxygen species (ROS) and nitric oxide (NO), a drop of the mitochondrial membrane potential, and a stimulation of caspase-3/7 activity. Exposure of H2O2-treated cells to Hb was accompanied by marked attenuations of ROS and NO surproductions, mitochondrial membrane potential reduction, and caspase-3/7 activity increase. The protective action of Hb was blocked by the protein kinase A (PKA) inhibitor H89, the protein kinase C (PKC) inhibitor chelerythrine, and the mitogen-activated protein (MAP)-kinase kinase (MEK) inhibitor U0126. Taken together, these data demonstrate for the first time that Hb is a glioprotective factor that protects astrocytes from apoptosis induced by oxidative stress and suggest that Hb may confer neuroprotection in neurodegenerative diseases. The anti-apoptotic activity of Hb on astrocytes is mediated through the PKA, PKC, and MAPK transduction pathways and can be accounted for by inhibition of oxidative stress-induced mitochondrial dysfunctions and caspase activation.


Towards improved magnetic fluid hyperthermia: major-loops to diminish variations in local heating.
In the context of using magnetic nanoparticles for heat-mediated applications, the need of an accurate knowledge of the local (at the nanoparticle level) heat generation in addition to the usually studied global counterpart has been recently highlighted. Such a need requires accurate knowledge of the links among the intrinsic particle properties, system characteristics and experimental conditions. In this work we have investigated the role of the particles' anisotropy polydispersity in relation to the amplitude (Hmax) of the AC magnetic field using a Monte Carlo technique. Our results indicate that it is better to use particles with large anisotropy for enhancing global heating, whereas for achieving homogeneous local heating it is better to use lower anisotropy particles. The latter ensures that most of the system undergoes major-loop hysteresis conditions, which is the key-point. This is equivalent to say that low-anisotropy particles (i.e. with less heating capability) may be better for accurate heat-mediated applications, which goes against some research trends in the literature that seek for large anisotropy (and hence heating) values.