Biovalorisation of crude glycerol and xylose into xylitol by oleaginous yeast Yarrowia lipolytica.
Xylitol is a commercially important chemical with multiple applications in the food and pharmaceutical industries. According to the US Department of Energy, xylitol is one of the top twelve platform chemicals that can be produced from biomass. The chemical method for xylitol synthesis is however, expensive and energy intensive. In contrast, the biological route using microbial cell factories offers a potential cost-effective alternative process. The bioprocess occurs under ambient conditions and makes use of biocatalysts and biomass which can be sourced from renewable carbon originating from a variety of cheap waste feedstocks. In this study, biotransformation of xylose to xylitol was investigated using Yarrowia lipolytica, an oleaginous yeast which was firstly grown on a glycerol/glucose for screening of co-substrate, followed by media optimisation in shake flask, scale up in bioreactor and downstream processing of xylitol. A two-step medium optimization was employed using central composite design and artificial neural network coupled with genetic algorithm. The yeast amassed a concentration of 53.2 g/L xylitol using pure glycerol (PG) and xylose with a bioconversion yield of 0.97 g/g. Similar results were obtained when PG was substituted with crude glycerol (CG) from the biodiesel industry (titer: 50.5 g/L; yield: 0.92 g/g). Even when xylose from sugarcane bagasse hydrolysate was used as opposed to pure xylose, a xylitol yield of 0.54 g/g was achieved. Xylitol was successfully crystallized from PG/xylose and CG/xylose fermentation broths with a recovery of 39.5 and 35.3%, respectively. To the best of the author's knowledge, this study demonstrates for the first time the potential of using Y. lipolytica as a microbial cell factory for xylitol synthesis from inexpensive feedstocks. The results obtained are competitive with other xylitol producing organisms.


Condylocephalic nails versus extramedullary implants for extracapsular hip fractures.
Condylocephalic nails are intramedullary nails which are inserted up through the femoral canal from above the knee, for example Ender and Harris nails. To compare condylocephalic nails with alternative implants (extramedullary implants such as fixed nail plates and sliding hip screws, or other intramedullary nails) for the treatment of extracapsular hip fracture in adults. We searched the Cochrane Musculoskeletal Injuries Group trials register, Medline (1983 to August 1999) and reference lists of relevant articles. Date of the most recent search: August 1999. Randomised or quasi-randomised trials comparing condylocephalic nails with other implants. All reviewers independently assessed trial quality and extracted data. Data were pooled where relevant and possible. Ender nails and Harris nail data were presented separately. Results from fixed nail plates and sliding hip screws were sub-grouped to explore differences in these two implant types. Eleven trials were included. Ten compared Ender nails with either a fixed nail plate or a sliding hip screw. One compared the Harris condylocephalic nail with a sliding hip screw. The only advantages of condylocephalic nails were a reduced deep wound sepsis rate (0.9% versus 4.2%; odds ratio 0.26, 95% confidence interval 0.12 to 0.56), length of surgery and operative blood loss. However there was an increased risk of re-operation (20.9% versus 5. 5%; odds ratio 3.78, 95% confidence interval 2.67 to 5.36) and later fracture of the femur when compared with extramedullary implants. There was also an increased risk of cut-out of the implant from the femoral head for Ender nails compared with the sliding hip screw, but not for fixed nail plates. Backing out of the nail was a frequent complication (30%) of Ender nails and often resulted in revision surgery. Ender nails also had an increased risk of shortening of the leg and external rotation deformity and potentially a poorer return to previous walking ability. An increase in residual pain resulting from an excess of knee pain was also evident in patients undergoing condylocephalic nailing. There was no apparent difference in mortality between the condylocephalic nail and extramedullary implant groups. Any advantages in intra-operative outcomes of condylocephalic nails are outweighed by the increase in fracture healing complications, re-operation rate, residual pain and limb deformity when compared with an extramedullary implant, particularly a sliding hip screw. The use of condylocephalic nails (in particular Ender nails), for trochanteric fracture is no longer appropriate.


Graphical analysis of 6-fluoro-L-dopa trapping: effect of inhibition of catechol-O-methyltransferase.
Graphical methods to analyze tracer time-course data allow reliable quantitation of the rate of incorporation of tracer from plasma into a "trapped" kinetic component, even when the details of the kinetic model are unknown. Applications of the method over long time periods often expose the slow reversibility of the trapping process. In the extended graphical method, both trapping rate and a presumed first-order loss rate constant are estimated simultaneously from the time-course data. We applied the extended graphical method to 6-fluoro-L-dopa (6-FD), simultaneously estimating the rate of uptake (Ki) and the rate constant for loss from the trapped component (K(loss)) in a single fitting procedure. We applied this approach to study the effects of two catechol-O-methyl-transferase inhibitors on the kinetics of 6-FD in cynomolgus monkeys. Inhibition of peripheral O-methylation with either inhibitor, confirmed by high-performance liquid chromatography analysis of labeled compounds in arterial plasma, had no significant effect on Ki, in agreement with previously reported studies. In contrast, tolcapone, a catechol-O-methyl-transferase inhibitor, having central effects in addition to peripheral effects at the dosage used, decreased K(loss) by 40% from control values (p < 0.002), whereas nitecapone, which has no known central activity, had no significant effect. This method provides insight into the neurochemical basis for the kinetic behavior of 6-FD in both health and disease and may be used to define the action of centrally active drugs that influence the metabolism of dopamine.


Noninvasive determination of local cerebral metabolic rate of glucose in man.
A method for the determination of local cerebral metabolic rates of glucose (LCMRGlc) in normal man is described. The method employs [18F]2-fluoro-2-deoxy-D-glucose (FDG) and emission-computed tomography (ECT). FDG was injected intravenously as a bolus. Radioactivities in separate brain regions were measured with ECT. Plasma FDG concentration following injection was measured from blood samples. A mathematical model that describes the kinetics of FDG transports was employed to determine the transport rate constants of FDG and to convert the radioactivity measurements to metabolic rates. The model has taken into account the possible dephosphorylation reaction from FDG-6-PO4 (FDG-6-P) to free FDG in brain tissues. Experiments were performed in 13 normal volunteers. The rate constants of FDG in man were found to be comparable to those of deoxyglucose in rat and in rhesus monkey. The average LCMRGlc in gray and in white matter were found to be 7.30 +/- 1.18 (SD) and 3.41 +/- 0.64 mg/min per 100 g brain tissue, respectively. The subject-to-subject variation of LCMRGlc as measured by the present method was comparable to those of other methods that measure whole-brain CMRGlc.


Incapacitated rape and alcohol use in White and Asian American college women.
This study examined the role of Asian ethnicity as a moderator of drinking outcomes associated with alcohol-related sexual assault (incapacitated rape). Participants were 5,467 Asian American and White college women. Results found the overall MANOVA for ethnicity and incapacitated rape (IR) interactions to be significant. Asian American participants with no history of IR had fewer drinking problems than White American participants with no history of IR. Asian American participants with IR histories had more drinking problems than White Americans with IR histories. Findings indicate Asian Americans who experience IR may be at increased risk for negative alcohol outcomes.


The Utility of a Connecting Framework to Facilitate Understanding of and Reduce the Disparities in Hospice Care Experienced by Racial and Ethnic Minorities.
Rapidly changing demographics in the United States and diverse cultural beliefs impact hospice utilization and end-of-life care. Healthcare professionals and clinicians need a connecting framework to understand patients' and their family's perspectives regarding utilization of those services. This framework will assist healthcare workers in providing culturally sensitive and appropriate information to patients nearing the end of life, so that they and their loved ones can make informed decisions for optimal care during this passage of life. Considering the variables in this framework may also help facilitate communication between healthcare professionals and patients and reduce misunderstanding among the surviving family members.


Circulation of avian influenza H5N1 in live bird markets in Egypt.
The poultry meat trade in Egypt depends mainly on live bird markets (LBMs) because of insufficient slaughterhouses, lack of marketing infrastructure, and cultural preference for consumption of freshly slaughtered poultry. There are two types of LBMs in Egypt: retail shops and traditional LBMs where minimal, if any, food safety standards or veterinary inspection are implemented. Before January 2009, LBMs were considered to be a missing link in the epidemiology of avian influenza in Egypt. This incited us to initiate this surveillance to better understand the perpetuation of H5N1 and the risk of infection in poultry markets. Seventy-one out of 573 (12.4%) examined LBMs were positive for the H5N1 subtype by real-time--quantitative polymerase chain reaction (RT-qPCR) from January to April 2009. Where a 70.4% detection rate from LBMs had waterfowl only as a solitary sold species, a 26.8% detection rate from LBMs had waterfowl mixed with chicken and/or turkey, and 2.8% from LBMs had only turkey. Higher incidence, 40.8%, of positive LBMs was recorded during the cold month of February and concentrated mainly in the highly populated Nile Delta. These findings revealed wide circulation of H5N1 avian influenza virus in LBMs in Egypt, which poses a threat to public health and the poultry industry. Long-term control measures are required, and routine surveillance of bird markets should be conducted year-round.


Profile of blinatumomab and its potential in the treatment of relapsed/refractory acute lymphoblastic leukemia.
The CD19 marker is expressed on the surface of normal and malignant immature or mature B-cells. On the other hand, immunotherapy involving T-cells is a promising modality of treatment for many neoplastic diseases including leukemias and lymphomas. The CD19/CD3-bispecific T-cell-engaging (BiTE(®)) monoclonal antibody blinatumomab can transiently engage cytotoxic T-cells to CD19+ target B-cells inducing serial perforin-mediated lysis. In the first clinical trial, blinatumomab showed efficacy in non-Hodgkin's lymphomas, but the most important trials have been conducted in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and in ALL with minimal residual disease. Encouraging reports on the activity of blinatumomab in R/R Philadelphia chromosome-negative B-cell precursor ALL led to its approval by the US Food and Drug Administration on December 3, 2014 after an accelerated review process. This review focuses on the profile of blinatumomab and its activity in R/R ALL.


[Having the best intentions is necessary but not sufficient--quality dimensions for early childhood interventions].
Early childhood interventions are a promising strategy to improve the development of children in socially disadvantaged families and to reduce their risk for abuse and neglect. However, proven effects are small with substantial variations between existing programs depending on differences in program planning and implementation. On the basis of international findings on the effectiveness of early childhood intervention, health promotion, and implementation research, we provide an overview of different quality aspects in the development, implementation, and evaluation of early childhood interventions, and a framework for future quality assessment of early childhood intervention programs in Germany. Scaling up of these programs should be accompanied by intensive quality assessment and development in order to achieve the intended outcomes.


The epidemiology and economic impact of varicella-related hospitalizations in Turkey from 2008 to 2010: a nationwide survey during the pre-vaccine era (VARICOMP study).
Varicella can cause complications that are potentially serious and require hospitalization. Our current understanding of the causes and incidence of varicella-related hospitalization in Turkey is limited and sufficiently accurate epidemiological and economical information is lacking. The aim of this study was to estimate the annual incidence of varicella-related hospitalizations, describe the complications, and estimate the annual mortality and cost of varicella in children. VARICOMP is a multi-center study that was performed to provide epidemiological and economic data on hospitalization for varicella in children between 0 and 15 years of age from October 2008 to September 2010 in Turkey. According to medical records from 27 health care centers in 14 cities (representing 49.3% of the childhood population in Turkey), 824 children (73% previously healthy) were hospitalized for varicella over the 2-year period. Most cases occurred in the spring and early summer months. Most cases were in children under 5 years of age, and 29.5% were in children under 1 year of age. The estimated incidence of varicella-related hospitalization was 5.29-6.89 per 100,000 in all children between 0-15 years of age in Turkey, 21.7 to 28 per 100,000 children under 1 year of age, 9.8-13.8 per 100,000 children under 5 years of age, 3.96-6.52 per 100,000 children between 5 and 10 years of age and 0.42 to 0.71 per 100,000 children between 10 and 15 years of age. Among the 824 children, 212 (25.7%) were hospitalized because of primary varicella infection. The most common complications in children were secondary bacterial infection (23%), neurological (19.1%), and respiratory (17.5%) complications. Secondary bacterial infections (p < 0.001) and neurological complications (p < 0.001) were significantly more common in previously healthy children, whereas hematological complications (p < 0.001) were more commonly observed in children with underlying conditions. The median length of the hospital stay was 6 days, and it was longer in children with underlying conditions (<0.001). The median cost of hospitalization per patient was $338 and was significantly higher in children with underlying conditions (p < 0.001). The estimated direct annual cost (not including the loss of parental work time and school absence) of varicella-related hospitalization in children under the age of 15 years in Turkey was $856,190 to $1,407,006. According to our estimates, 882 to 1,450 children are hospitalized for varicella each year, reflecting a population-wide occurrence of 466-768 varicella cases per 100,000 children. In conclusion, this study confirms that varicella-related hospitalizations are not uncommon in children, and two thirds of these children are otherwise healthy. The annual cost of hospitalization for varicella reflects only a small part of the overall cost of this disease, as only a very few cases require hospital admission. The incidence of this disease was higher in children <1 year of age, and there are no prevention strategies for these children other than population-wide vaccination. Universal vaccination is therefore the only realistic option for the prevention of severe complications and deaths. The surveillance of varicella-associated complications is essential for monitoring of the impact of varicella immunization.


Antibiotics are associated with lower relapse rates in outpatients with acute exacerbations of COPD.
COPD is a complex disease with exacerbations characterized by worsening of symptoms resulting in deteriorating lung function. To assess predictive factors of relapse for patients with acute exacerbations of COPD (AECB). Retrospective cohort analysis of visits for AECB. Veterans Affairs Medical Center. Three hundred sixty-two visits (173 patients) with documented COPD treated as outpatients for AECB. Severity of underlying COPD, severity of AECB, comorbid conditions, therapy, and relapse rates (return visit within 14 days with persistent or worsening symptoms). Each visit was analyzed individually (referred to as a patient-visit). One group received antibiotics (270 patient-visits), and the second group (92 patient-visits) did not. Both groups had similar demographics and severity of underlying COPD. The overall relapse rate was 22%. The majority of patient-visits (95%) with severe symptoms at presentation were prescribed antibiotics vs only 40% of those with mild symptoms. Twenty-nine of 92 patient-visits (32%) were followed by relapse in the group that was not given antibiotics, whereas only 50 of 270 (19%) treated with antibiotics relapsed (p < 0.001). Those treated with amoxicillin had an even higher relapse rate (20 of 37 patient-visits, or 54%) than those who did not receive antibiotics (p = 0.006). Relapse from AECB was not related to the severity of underlying disease or to the severity of the acute exacerbation. Patients treated with antibiotics had significantly lower relapse rates than those who did not receive antibiotics. However, the specific choice of antibiotic is important because those treated with amoxicillin had the highest relapse rates of all groups.


Wnt/β-Catenin-Signaling Modulates Megakaryopoiesis at the Megakaryocyte-Erythrocyte Progenitor Stage in the Hematopoietic System.
The bone marrow (BM) hematopoietic system (HS) gives rise to blood cells originating from hematopoietic stem cells (HSCs), including megakaryocytes (MKs) and red blood cells (erythrocytes; RBCs). Many steps of the cell-fate decision remain to be elucidated, being important for cancer treatment. To explore the role of Wnt/β-catenin for MK and RBC differentiation, we activated β-catenin signaling in platelet-derived growth factor b (Pdgfb)-expressing cells of the HS using a Cre-lox approach (Ctnnb1BM-GOF). FACS analysis revealed that Pdgfb is mainly expressed by megakaryocytic progenitors (MKPs), MKs and platelets. Recombination resulted in a lethal phenotype in mutants (Ctnnb1BM-GOFwt/fl, Ctnnb1BM-GOFfl/fl) 3 weeks after tamoxifen injection, showing an increase in MKs in the BM and spleen, but no pronounced anemia despite reduced erythrocyte counts. BM transplantation (BMT) of Ctnnb1BM-GOF BM into lethally irradiated wildtype recipients (BMT-Ctnnb1BM-GOF) confirmed the megakaryocytic, but not the lethal phenotype. CFU-MK assays in vitro with BM cells of Ctnnb1BM-GOF mice supported MK skewing at the expense of erythroid colonies. Molecularly, the runt-related transcription factor 1 (RUNX1) mRNA, known to suppress erythropoiesis, was upregulated in Ctnnb1BM-GOF BM cells. In conclusion, β-catenin activation plays a key role in cell-fate decision favoring MK development at the expense of erythroid production.


Accuracy of Continuous Glucose Monitoring before, during, and after Aerobic and Anaerobic Exercise in Patients with Type 1 Diabetes Mellitus.
Continuous glucose monitoring (CGM) plays an important role in treatment decisions for patients with type 1 diabetes under conventional or closed-loop therapy. Physical activity represents a great challenge for diabetes management as well as for CGM systems. In this work, the accuracy of CGM in the context of exercise is addressed. Six adults performed aerobic and anaerobic exercise sessions and used two Medtronic Paradigm Enlite-2 sensors under closed-loop therapy. CGM readings were compared with plasma glucose during different periods: one hour before exercise, during exercise, and four hours after the end of exercise. In aerobic sessions, the median absolute relative difference (MARD) increased from 9.5% before the beginning of exercise to 16.5% during exercise (p < 0.001), and then decreased to 9.3% in the first hour after the end of exercise (p < 0.001). For the anaerobic sessions, the MARD before exercise was 15.5% and increased without statistical significance to 16.8% during exercise realisation (p = 0.993), and then decreased to 12.7% in the first hour after the cessation of anaerobic activities (p = 0.095). Results indicate that CGM might present lower accuracy during aerobic exercise, but return to regular operation a few hours after exercise cessation. No significant impact for anaerobic exercise was found.


In2O3/Bi2S3 S-scheme Heterojunction-Driven Molecularly Imprinted Photoelectrochemical Sensor for Ultrasensitive Detection of Florfenicol.
Florfenicol (FF) raises significant human health and environmental concerns due to its toxicity to the hematology system and the potential spread of antibiotic-resistant genes. Here, a highly sensitive molecularly imprinted photoelectrochemical (PEC) sensor, featuring an In2O3/Bi2S3 S-scheme heterojunction, is proposed to detect FF without an external voltage supply. Compared with conventional II-type heterojunctions, S-scheme heterojunctions efficiently promote carrier separation and enhance the redox capability of the photocatalytic system. This allows more dissolved O2 and H2O molecules to participate in the redox reaction, resulting in an amplified and stabilized photocurrent response. The electron transfer in the S-scheme heterojunction is confirmed via electron spin resonance (ESR). With the molecular imprinting technique, this PEC platform exhibits exceptional selectivity, wide linear range (1.0 × 10-4-1.0 × 104 ng mL-1), low detection limit (6.4 × 10-5 ng mL-1), and applicability in real milk and chicken samples. This work not only showcases a PEC platform for accurately and portably detecting drugs but also proposes a viable approach for designing S-scheme heterojunctions in sensing analysis.


Super-resolution imaging in live Caulobacter crescentus cells using photoswitchable EYFP.
The commonly used, monomeric EYFP enabled imaging of intracellular protein structures beyond the optical resolution limit ('super-resolution' imaging) in living cells. By combining photoinduced activation of single EYFP fusions and time-lapse imaging, we obtained sub-40 nm resolution images of the filamentous superstructure of the bacterial actin protein MreB in live Caulobacter crescentus cells. These studies demonstrated that EYFP is a useful emitter for in vivo super-resolution imaging.


An Interventionalist's Guide to Hemoptysis in Cystic Fibrosis.
Massive hemoptysis occurs in a minority of patients with cystic fibrosis, with an annual incidence of 1%. Although rare, massive hemoptysis can be a severe and potentially fatal complication of this disease. Beyond the acute life-threatening event, hemoptysis in patients with cystic fibrosis has been associated with faster decline in lung function, accelerated need for lung transplant, and increased mortality. The bronchial arteries are the culprit vessels in over 90% of cases of hemoptysis. This normally quiescent vascular system undergoes remarkable hypertrophy, collateralization, and angiogenesis before the onset of hemoptysis, introducing numerous pitfalls for the interventionalist. However, in experienced hands, bronchial artery embolization is a safe and potentially lifesaving therapy. Preprocedural noninvasive imaging, specifically computed tomographic angiography, has been repeatedly validated for helping to localize the likely site of bleeding, characterizing pertinent arterial anatomy, and promoting efficient and effective intervention; it has been recommended for all stable patients with hemoptysis. Success in the angiographic suite requires a thorough understanding of normal and variant bronchial arterial anatomy, appropriate patient selection, and a meticulous embolization technique. A meticulous approach to imaging and intervention, conscientious of both visualized and nonvisualized collateral pathways and nontarget vessels, can minimize potentially devastating complications. This review summarizes the current literature, modern procedural techniques, and emerging controversies, serving to guide an evolving approach to management of patients with cystic fibrosis and hemoptysis. ©RSNA, 2018.


Treatment of Cracked Teeth.
Although many options are proposed for the treatment of cracked posterior teeth, most treatment decisions are not evidence based. Thus, considerable individual variation can occur regarding treatment recommendations for the same scenario. To our knowledge, there are no studies in the literature assessing practitioners' attitudes toward the treatment of cracked teeth. This research recorded variations between general practitioners and specialist groups regarding the treatment approaches of cracked teeth. In a cross-sectional structured questionnaire survey, 32 prosthodontists, 34 endodontists, and 29 general practitioners working in public and private dental health services in Kuwait were assessed regarding their treatment approach to 5 different clinical cracked tooth scenarios. Chosen treatment options varied greatly. Within each scenario, there was a wide range in treatment preferences across all groups and within each group, especially with respect to asymptomatic cracked teeth. Overall, treatment approaches did not relate to specialty training. Statistically significant differences were noticed between endodontists and general practitioners, in case of crowning teeth, in scenario 3 (P = .032), and in extracting teeth for scenario 5 (P = .048). This study highlights that, despite suggested guidelines, there are large differences in the approach to treatment planning for cracked teeth by practitioners and specialists, both as a whole and within each group. Further multicountry studies involving larger dental populations are needed to determine factors that influence practitioners' treatment choices and/or whether better or more widely accepted guidelines need to be established. More prospective well-controlled clinical case-based research with long-term follow-ups is required.


Cloning and physical mapping of an early region of the bacteriophage T4 genome.
We have cloned DNA restriction fragments from the largely nonessential region of bacteriophage T4 located between genes 39 and 56. The cloned DNA fragments were used to construct a precise map of the sites in this region recognized by eight restriction endonucleases. This restriction map allowed us to compare the cytosine-containing T4 DNA used for cloning with the hydroxymethylcytosine-containing DNA of wild-type T4; there were no detectable rearrangements in the region tested. We were also able to determine the physical locations of several deletion end points and of several genes.


Tuberculosis of breast (study of 7 cases).
Seven cases of tuberculosis of breast are presented. The clinical features were multiple discharging sinuses, lump, ulcer and recurring abscess of breast. Diagnosis relied on histological appearance. Acid fast bacilli being present in only one specimen and positive culture obtained in one patient. Successful treatment combines antituberculous drug therapy with removal of infected breast tissue.


GTP cyclohydrolase I is coinduced in hepatocytes stimulated to produce nitric oxide.
GTP cyclohydrolase I is the rate-controlling enzyme in the production of tetrahydrobiopterin (BH(4)), an essential cofactor for nitric oxide (NO) synthase. Here we show that GTP cyclohydrolase I mRNA was present in unstimulated hepatocytes and was up-regulated 2- to 3-fold concurrently with iNOS induction induced in vivo by LPS injection and in vitro by stimulation with LPS and inflammatory cytokines tumor necrosis factor alpha, interleukin-1 beta, and interferon-gamma. Hepatocyte GTP cyclohydrolase I enzyme activity increased 2-fold in vivo after LPS. This coinduction of GTP cyclohydrolase I resulted in increased total intracellular biopterin which supported induced NO synthesis. The addition of a GTP cyclohydrolase I inhibitor to the stimulated hepatocytes decreased intracellular biopterin levels and resulted in a decrease in NO production. The results show that GTP cyclohydrolase I is up-regulated by certain acute inflammatory conditions. Further, the results indicate that biopterin is essential as a cofactor for induced NO synthase activity in hepatocytes.


[Individual typological peculiarities of system blood flow, physical capacity for work and cardiac activity regulation in patients with different resistance to periodontal diseases].
From position of typological variability of physiological individuality concept-functional constitution types - the principle of organism integrity was substantiated for stomatological pathology. There were isolated typical and specific reactions of cardiac-vessel system in patients with different resistance to periodontal diseases. Each functional type - patients with different levels of usual motion activity - had their own physiological peculiarities of parameters of system blood flow, physical capacity for work and cardiac activity regulation, that determined individual typological organism reaction in cases of maxillo-facial system pathology. The received data gives the objective base for physiological approach to single out the extreme variants of norm for forming risk contingent and groups of resistant people to periodontal diseases.


Itk functions to control actin polymerization at the immune synapse through localized activation of Cdc42 and WASP.
Actin polymerization at the immune synapse is required for T cell activation and effector function; however, the relevant regulatory pathways remain poorly understood. We showed previously that binding to antigen presenting cells (APCs) induces localized activation of Cdc42 and Wiskott-Aldrich Syndrome protein (WASP) at the immune synapse. Several lines of evidence suggest that Tec kinases could interact with WASP-dependent actin regulatory processes. Since T cells from Rlk-/-, Itk-/-, and Rlk-/- x Itk-/- mice have defects in signaling and development, we asked whether Itk or Rlk function in actin polymerization at the immune synapse. We find that Itk-/- and Rlk-/- x Itk-/- T cells are defective in actin polymerization and conjugate formation in response to antigen-pulsed APCs. Itk functions downstream of the TCR, since similar defects were observed upon TCR engagement alone. Using conformation-specific probes, we show that although the recruitment of WASP and Arp2/3 complex to the immune synapse proceeds normally, the localized activation of Cdc42 and WASP is defective. Finally, we find that the defect in Cdc42 activation likely stems from a requirement for Itk in the recruitment of Vav to the immune synapse. Our results identify Itk as a key element of the pathway leading to localized actin polymerization at the immune synapse.


Apatite microtopographies instruct signaling tapestries for progenitor-driven new attachment of teeth.
Dimension and structure of extracellular matrix surfaces have powerful influences on cell shape, adhesion, and gene expression. Here we show that natural tooth root topographies induce integrin-mediated extracellular matrix signaling cascades in tandem with cell elongation and polarization to generate physiological periodontium-like tissues. In this study we replanted surface topography instructed periodontal progenitors into rat alveolar bone sockets for 8 and 16 weeks, resulting in complete reattachment of tooth roots to the surrounding alveolar bone with a periodontal fiber apparatus closely matching physiological controls along the entire root surface. Displacement studies and biochemical analyses confirmed that progenitor-based engineered periodontal tissues were similar to control teeth and uniquely derived from preimplantation green fluorescent protein (GFP)-labeled progenitors. Together, these studies illustrate the capacity of natural extracellular surface topographies to instruct progenitor cell populations to fully regenerate complex cellular and structural morphologies of tissues once lost to disease. We suggest that our strategy could be used for the replantation of teeth lost due to trauma or as a novel approach for tooth replacement using tooth-shaped replicas.


Delineation of the preferences and requirements of the human immunodeficiency virus type 1 dimerization initiation signal by using an in vivo cell-based selection approach.
HIV-1 packages two copies of RNA into one particle, and the dimerization initiation signal (DIS) in the viral RNA plays an important role in selecting the copackaged RNA partner. We analyzed the DIS sequences of the circulating HIV-1 isolates in the GenBank database and observed that, in addition to the prevalent GCGCGC, GTGCAC, and GTGCGC sequences, there are many other minor variants. To better understand the requirements for the DIS to carry out its function, we generated a plasmid library containing a subtype B HIV-1 genome with a randomized DIS, infected cells with viruses derived from the library, and monitored the emergence of variants at different time points until 100 days postinfection. We observed rapid loss of viral diversity and found that the selected variants contained palindromes in the DIS. The "wild-type" GCGCGC-containing virus was a major variant, whereas GTGCAC- and GTGCGC-containing viruses were present at low frequencies. Additionally, other 6-nucleotide (nt) palindromic sequences were selected; a major category of the selected variants contained two GC dyads in the center of the palindrome, flanked by a non-GC dyad. Surprisingly, variants with GC-rich 4-nt palindromes were sustained throughout the selection period at significant frequencies ( approximately 12 to 38%); of these, variants containing the CGCGC sequence were observed frequently, suggesting that this sequence has a selection advantage. These results revealed that multiple sequences can fulfill the function of the HIV-1 DIS. A common feature of the selected DIS sequence is a 4- or 6-nt GC-rich palindrome, although not all sequences with these characteristics were selected, suggesting the presence of other unidentified interactions.


Bacterial biofilm formation, encrustation, and antibiotic adsorption to ureteral stents indwelling in humans.
Encrustation and urinary tract infection are problematic complications of ureteral stent usage. The objective of our first study was to use surface science techniques to examine three ureteral stent types for encrustation, biofilm formation, and antibiotic adsorption after use in patients. Black Beauty (N = 16), LSe (N = 16), and SofFlex (N = 32) ureteral stents were recovered from patients who had received trimethoprim or ciprofloxacin while the stent was indwelling. These stents were examined with X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy/energy-dispersive X-ray analysis (SEM/EDX) for the presence and composition of encrustation or biofilm. Conditioning films and encrustations were found on all stents. Encrustation elements (Ca, Mg, P) were identified on 11 of 16 Black Beauty (69%), 7 of 16 LSe (44%), and 12 of 32 SofFlex (38%) stents. The stent type, duration of insertion, and age or sex of the patient did not correlate significantly with the amount of encrustation. Bacterial biofilms were found on 1 of 7 Black Beauty stents (14%) and 7 of 32 SofFlex stents (22%). In a second study, an additional 28 patients with SofFlex stents were treated with ciprofloxacin (N = 16) or ofloxacin (N = 12). Their stents were subjected to high-performance liquid chromatography to determine if oral antibiotic therapy can lead to drug adsorption to the stent. Analysis showed that both ciprofloxacin and ofloxacin adsorbed to the stent surfaces. The mean concentrations of the two antibiotics within the conditioning film of the stents were 0.99 microg/mL and 0.34 microg/mL, respectively. These surface science techniques provide a comprehensive method of evaluating ureteral stents and other prosthetic devices in vivo.


Evidence for early membrane antigens in cytomegalovirus-infected cells.
Human cytomegalovirus (HCMV) induces membrane antigens (MA) which are detectable by immunofluorescent techniques as early as 24 h after infection. These antigens appear on the surface of infected cells in non-permissive human epithelioid and animal cells in addition to permissive human cells. The synthesis of the MA occurs in the presence of a DNA synthesis inhibitor, whereas RNA and protein synthesis inhibitors prevent its formation completely. These results demonstrate that the MA is a newly synthesized protein coded by an early function of the viral genome.


Dihydrobiopterin synthesis defect: an adult with diurnal fluctuation of symptoms.
A deficiency of dihydrobiopterin synthesis was found in a 27-year-old man with mild mental retardation, rigid spasticity, hyperreflexia, dystonia, myoclonus, and delay in the initiation of action, since age 10. Symptoms improved after sleep. Urine contained large amounts of neopterin and a trace of biopterin. Dihydropteridine reductase activity in red blood cells was normal. CSF levels of HVA and 5-HIAA were low. Tetrahydrobiopterin administration lowered serum phenylalanine and improved the symptoms.


Test Conditions in Macular Visual Field Testing in Glaucoma.
The purpose of this study is to evaluate the suitable visual field (VF) test conditions (target size, test type, and eccentricity) for the macular region, we investigated the correlations between the ganglion cell layer (GCL) thickness and 6 VF test results. We tested 32 eyes of patients (61.1±9.2 y) with preperimetric (6), early-stage (16), and moderate-stage (10) glaucoma. The VF tests included 3 SAP (the 10-2 HFA using SITA with target size III [HFA SITA (III)], full threshold with size III [HFA FULL (III)] and size I [HFA FULL (I)]) and 3 visual function-specific perimetry tests (the 10-2 SWAP, 10-2 flicker, and 10-2 Humphrey Matrix). The GCL and inner plexiform layer (GCL+IPL) thickness was measured by Spectral Domain Optical Coherence Tomography (SD-OCT) with a macular 7×7 mm cube scan (3D OCT-2000, Topcon). The coefficient of determination (r) for the correlation between visual sensitivity and the GCL+IPL thickness was calculated for each test at eccentricities 0 to 5 degrees, 5 to 7 degrees, and 7 to 10 degrees using linear and quadratic regressions. All 6 tests showed the strongest correlation with the GCL+IPL thickness at 5 to 7 degrees. The respective r (linear) and R (quadratic) for HFA SITA (III), HFA FULL (III), HFA FULL (I), SWAP, Flicker, and Matrix were (0.40, 0.50), (0.43, 0.53), (0.44, 0.46), (0.51, 0.51), (0.33, 0.34), and (0.52, 0.52). As compared with the frequently-used SAP with a size III, SAP with size I and the function-specific perimetry tests (especially the Matrix) could be more suitable for testing the macular region.


Effects of Methamphetamine on Testes Histopathology and Spermatogenesis Indices of Adult Male Rats.
Methamphetamine (MAMP) as a recreational drug has devastating effects on the central nervous system (CNS). Several studies have shown that MAMP has inhibitory effects on oogenesis and spermatogenesis, and causes impaired fertility. This study designed to investigate the effect of mAM Padministration on histological changes and spermatogenesis indices in the testis of adult male rats. In this experimental study, 50 male Wistar rats were randomly divided into control (received no treatment, n = 10), vehicle (received saline for 7 and 14 days, n = 20), and experimental group [received MAMP, 5 ml/kg, intraperitoneal (IP) for 7 and 14 days, n = 20]. Testicular tissue samples were stained by hematoxylin and eosin (H&E) technique. For histological study, we counted the number of spermatogonia, spermatocytes and Leydig cells. Spermatogenesis indices which include: tubular differentiation index (TDI), spermiogenesis index (SI), repopulation index (RI) and the mean seminiferous tubules diameter (MSTD) were studied. Data were analyzed by one-way ANOVA, using SPSS software. P < 0.05 was considered statistically significant. This study showed that MAMP caused a significant decrease in number of seminiferous tubules cells and spermatogenesis in treated group compared with the control group. Moreover, results showed a significant decrease in spermatogenesis indices including TDI, SI, RI, and MSTD in 14th day, compared to control group (P < 0.001). The data showed the adverse effects of MAMP administration (for 7 and 14 days) on testes structure and spermatogenesis indices in rat testis tissue. The underlying mechanism(s) needs further investigation.


The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is a genetic disease characterized by severe morbid obesity in association with hyperphagia and type 2 diabetes mellitus. Liraglutide is a glucagon-like peptide (GLP)-1 analog that controls appetite, decreases body weight and improves glycemic control. However, it is unclear if PWS patients with diabetes experience similar benefits of liraglutide therapy. In a 25 year-old female hyperglycemic PWS patient, liraglutide monotherapy improved her Hemoglobin A1c remarkably (12.6% to 6.1%) while steadily decreasing her body mass index (BMI: 39.1 kg/m(2) to 35.7 kg/m(2)). We offered this patient continued liraglutide therapy for one year to determine the effect on various metabolic parameters. Her hyperphagia was controlled soon after liraglutide treatment commenced and remained so throughout the treatment. The metabolic parameters changed as follows: visceral fat area fell from 150.1 to 113.2 (cm(2)); plasma insulin rose from 108.1 to 277.0 (pmol/L); plasma active GLP-1 dropped from 2.1 to 1.2 (fmol/L); plasma active ghrelin diminished from 137.0 to 27.7 (pmol/L). While plasma active ghrelin before treatment was abnormally high, even though her GLP-1 was normal, both decreased following liraglutide therapy. These results suggest that in addition to its insulinotropic effects, other potential mechanisms activated by liraglutide therapy may reduce the plasma ghrelin levels elevated in PWS, leading to an improvement in overeating, BMI and visceral fat, as well as glycemic control.


Increased incidence of malignancy in patients with primary hyperparathyroidism
Primary hyperparathyroidism (PHPT) is a disease that is diagnosed more frequently and generally in the asymptomatic period, with widely available biochemical tests. Evidence suggesting an association between PHPT and malignancy risk is increasing. Clarification of this association will be useful in PHPT for malignancy screening and management of patients with PHPT. In this study, we aimed to investigate the frequency of cancer in PHPT patients. A total of 775 PHPT patients were included in the retrospective study. Demographic, clinical and laboratory data of the patients were evaluated retrospectively. Malignancy was detected in 128 (16.50%) of 775 PHPT patients (female/male: 625/150). The mean age at diagnosis of PHPT was 57.99 ± 10.86 years, and the mean age at diagnosis of malignancy was 57.46 ± 11.17 years. Of the 128 patients with malignancy, 53 (41.40%) were diagnosed in the same year as PHPT. In terms of malignancy types, 51 (6.50%) of 775 PHPT patients had thyroid cancer. Thyroid cancer was followed by breast cancer (2.30%) and stomach cancer (1%) in order of frequency. We think that PHPT patients should be examined more carefully in terms of cancer risk, especially thyroid cancer. More comprehensive studies are needed to clarify the relationship between PHPT and cancer.


An immune-related gene prognostic risk index for pancreatic adenocarcinoma.
Our goal is to construct an immune-related gene prognostic risk index (IRGPRI) for pancreatic adenocarcinoma (PAAD), and to clarify the immune and molecular features in IRGPRI-defined PAAD subgroups and the benefit of immune checkpoint inhibitors (ICIs) therapy. Through differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and univariate Cox regression analysis, 16 immune-related hub genes were identified using the Cancer Genome Atlas (TCGA) PAAD dataset (n = 182) and immune gene set. From these genes, we constructed an IRGPRI with the Cox regression method and the IRGPRI was verified based on the Gene Expression Omnibus (GEO) dataset (n = 45). Then, we analyzed the immune and molecular features and the benefit of ICI therapy in IRGPRI-defined subgroups. Five genes, including S100A16, CD40, VCAM1, TNFRSF4 and TRAF1 were used to construct IRGPRI. As with the results of the GEO cohort, the overall survival (OS) was more favorable in low IRGPRI patients versus high IRGPRI patients. The composite results pointed out that low IRGPRI was associated with immune response-related pathways, high level of CTLA4, low KRAS and TP53 mutation rate, more infiltration of activated memory CD4+ T cells, CD8+ T cells, and more benefits from ICIs therapy. In comparison, high IRGPRI was associated with cancer-related pathways, low expression of CTLA4, high KRAS and TP53 mutation rate, more infiltration of M2 macrophages, and less benefit from ICIs therapies. This IRGPRI is an encouraging biomarker to define the prognosis, immune and molecular features, and benefits from ICIs treatments in PAAD.


Influence of disease activity and medications on offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus: a population-based study.
Exploring the associations between disease activity and medications with offspring birth weight, pre-eclampsia and preterm birth in systemic lupus erythematosus (SLE). Data from the Medical Birth Registry of Norway (MBRN) were linked with data from RevNatus, a nationwide observational register recruiting women with inflammatory rheumatic diseases. Singleton births in women with SLE included in RevNatus 2006-2015 were cases (n=180). All other singleton births registered in MBRN during this time (n=498 849) served as population controls. Z-score for birth weight adjusted for gestational age and gender was calculated. Disease activity was assessed using Lupus Activity Index in Pregnancy. We compared z-scores for birth weight, pre-eclampsia and preterm birth in cases with inactive disease, cases with active disease and population controls. Z-scores for birth weight in offspring were lower in inactive (-0.64) and active (-0.53) diseases than population controls (-0.11). Inactive disease did not predict pre-eclampsia while active disease yielded OR 5.33 and OR 3.38 compared with population controls and inactive disease, respectively. Preterm birth occurred more often in inactive (OR 2.57) and active (OR 8.66) diseases compared with population controls, and in active compared with inactive disease (OR 3.36). SLE has an increased odds for low birth weight and preterm birth, amplified by active disease. The odds for pre-eclampsia is elevated in active, but not inactive disease. This calls for tight follow-up targeting inactive disease before and throughout pregnancy.


Comparison of three infant venous reservoirs with vacuum-assisted venous drainage during varying levels of cardiotomy suction.
Vacuum-assisted venous drainage has gained widespread use within the pediatric perfusion community for use during cardiopulmonary bypass. It is questioned whether its efficiency may be compromised with application of excessive cardiotomy suction to the infant hard-shell venous reservoir. An in vitro simulation circuit was used to research this phenomenon. A comparison of three different infant hard-shell venous reservoirs also took place to determine if one reservoir type was more advantageous when handling cardiotomy suction. The reservoirs tested were the Maquet VHK 11000, Medtronic Affinity Pixie, and Terumo Capiox FX05. The in vitro simulation circuit consisted of a 1 L reservoir bag that was cannulated at one access point with an Edwards Lifesciences 10Fr aortic cannula and the other access area with an Edwards Lifesciences 10Fr right angle venous cannula and 12Fr right angle venous cannula that were joined together. Key points of measurement and response variables were the pressures on the connection of the venous cannulas, inlet of the venous reservoir, and flow through the venous line. Vacuum was applied and manipulated with a Maquet VAVD Controller to settings of -20 mmHg, -30 mmHg, -40 mmHg, -50 mmHg, and -60 mmHg. Cardiotomy suction was added at settings of 1 LPM, 2 LPM, 3 LPM, and 4 LPM. Values from each response variable were monitored and recorded. These data were utilized to compare the reservoirs with a random coefficient model for each response variable. There is an adverse effect of excessive cardiotomy suction on the efficacy of vacuum-assisted venous drainage in infant hard-shell venous reservoirs. There is no significant difference between the VHK 11000, Pixie, and FX05 regarding their ability to handle this occurrence. An important discovery was that the FX05 showed a greater transfer of vacuum to the venous cannulas and reservoir inlet.


Interaction between 2 extracellular loops influences the activity of the cystic fibrosis transmembrane conductance regulator chloride channel.
Activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is thought to be controlled by cytoplasmic factors. However, recent evidence has shown that overall channel activity is also influenced by extracellular anions that interact directly with the extracellular loops (ECLs) of the CFTR protein. Very little is known about the structure of the ECLs or how substances interacting with these ECLs might affect CFTR function. We used patch-clamp recording to investigate the accessibility of cysteine-reactive reagents to cysteines introduced throughout ECL1 and 2 key sites in ECL4. Furthermore, interactions between ECL1 and ECL4 were investigated by the formation of disulfide crosslinks between cysteines introduced into these 2 regions. Crosslinks could be formed between R899C (in ECL4) and a number of sites in ECL1 in a manner that was dependent on channel activity, suggesting that the relative orientation of these 2 loops changes on activation. Formation of these crosslinks inhibited channel function, suggesting that relative movement of these ECLs is important to normal channel function. Implications of these findings for the effects of mutations in the ECLs that are associated with cystic fibrosis and interactions with extracellular substances that influence channel activity are discussed.


Reperfusion within 6 hours outperforms recanalization in predicting penumbra salvage, lesion growth, final infarct, and clinical outcome.
The relative merits of reperfusion versus recanalization to predict tissue and clinical outcomes in anterior circulation stroke have been previously assessed using data acquired >12 hours postonset. To avoid late-occurring confounders such as non-nutritional reperfusion, futile recanalization and no-reflow phenomenon, we performed ultraearly assessment of reperfusion and recanalization. From a multicenter prospective database, 46 patients with acute magnetic resonance angiography-visible occlusion and in whom both reperfusion and recanalization were assessed on follow-up magnetic resonance imaging ≤6 hours of symptom onset were identified. Multiple linear regressions modeled salvaged penumbra, diffusion-weighted imaging lesion growth, and final infarct at 1 month using baseline clinical and imaging parameters and acute reperfusion or recanalization. Best predictors were determined with the Akaike information criterion. Univariate and multivariate logistic regressions identified the clinical and imaging predictors of clinical outcome. Admission magnetic resonance imaging showed M1 occlusion in 15 (33%) patients; median penumbra volume was 13.4 mL. Acute reperfusion was observed in 27 (59%) patients; 42% of nonrecanalized patients demonstrated reperfusion. The dichotomized classification of reperfusion and recanalization was discordant (P=0.0002). Reperfusion≤6 hours was a significant (P<0.05) predictor of increased penumbra salvage, reduced lesion growth, and final infarct size. Recanalization did not improve model accuracy. Reperfusion, but not recanalization, was significantly associated with good clinical outcome in logistic regressions. Reperfusion≤6 hours was consistently superior to recanalization in predicting tissue and clinical outcome. Reperfusion without recanalization was frequent and probably related to retrograde reperfusion through leptomeningeal collaterals. Acute reperfusion was the strongest predictor of, and may therefore, represent a reliable surrogate for, clinical outcome.


Safety and efficacy of modern insulin analogues.
A1chieve® was a noninterventional study evaluating the clinical safety and efficacy of biphasic insulin aspart 30, insulin detemir, and insulin aspart. Korean type 2 diabetes patients who have not been treated with the study insulin or have started it within 4 weeks before enrollment were eligible for the study. The patient selection and the choice of regimen were at the discretion of the physician. The safety and efficacy information was collected from the subjects at baseline, week 12, and week 24. The number of serious adverse drug reactions (SADRs) was the primary endpoint. The changes of clinical diabetic markers at week 12 and/or at week 24 compared to baseline were the secondary endpoints. Out of 4,058 exposed patients, 3,003 completed the study. During the study period, three SADRs were reported in three patients (0.1%). No major hypoglycemic episodes were observed and the rate of minor hypoglycemic episodes marginally decreased during 24 weeks (from 2.77 to 2.42 events per patient-year). The overall quality of life score improved (from 66.7±15.9 to 72.5±13.5) while the mean body weight was slightly increased (0.6±3.0 kg). The 24-week reductions in glycated hemoglobin, fasting plasma glucose and postprandial plasma glucose were 1.6%±2.2%, 2.5±4.7 mmol/L, and 4.0±6.4 mmol/L, respectively. The studied regimens showed improvements in glycemic control with low incidence of SADRs, including no incidence of major hypoglycemic episodes in Korean patients with type 2 diabetes.


Fluorescence lifetime imaging of free and protein-bound NADH.
We introduce a methodology, fluorescence lifetime imaging (FLIM), in which the contrast depends on the fluorescence lifetime at each point in a two-dimensional image and not on the local concentration and/or intensity of the fluorophore. We used FLIM to create lifetime images of NADH when free in solution and when bound to malate dehydrogenase. This represents a challenging case for lifetime imaging because the NADH decay times are just 0.4 and 1.0 ns in the free and bound states, respectively. In the present apparatus, lifetime images are created from a series of phase-sensitive images obtained with a gain-modulated image intensifier and recorded with a charge-coupled device (CCD) camera. The intensifier gain is modulated at the light-modulation frequency or a harmonic thereof. A series of stationary phase-sensitive images each obtained with various phase shifts of the gain-modulation signal, is used to determine the phase angle or modulation of the emission at each pixel, which is in essence the lifetime image. We also describe am imaging procedure that allows specific decay times to be suppressed, allowing in this case suppression of the emission from either free or bound NADH. Since the fluorescence lifetimes of probes are known to be sensitive to numerous chemical and physical factors such as pH, oxygen, temperature, cations, polarity, and binding to macromolecules, this method allows imaging of the chemical or property of interest in macroscopic and microscopic samples. The concept of FLIM appears to have numerous potential applications in the biosciences.


Dual-emissive polystyrene@zeolitic imidazolate framework-8 composite for ratiometric detection of singlet oxygen.
This work demonstrated the potential of zeolitic imidazolate framework-8 (ZIF-8) as a host for the co-encapsulation of multiple fluorescent cargos to fabricate fluorescent composites for ratiometric sensing. The one-pot self-assembly of 2-methylimidazole, zinc nitrate, 9-anthracenecarboxylic acid (AnC), and polystyrene sphere doped with europium chelate (EuPS) in methanol solution can lead to the formation of dual-emissive EuPS@AnC/ZIF-8 with excellent fluorescent activity. Based on the distinct fluorescent responses of Eu3+ and AnC to singlet oxygen (1O2), EuPS@AnC/ZIF-8 can be developed as a ratiometric sensor for 1O2 detection. In this ratiometric sensor, Eu3+ fluorescence was employed as a reference signal for providing built-in correction to avoid environmental effects, while AnC fluorescence served as a response signal to detect 1O2 because of its turn-off behavior upon reacting with 1O2. Benefiting from the confinement effect of the ZIF-8 host, the presented sensor showed high sensitivity toward 1O2 with a detection limit of 43 nM and excellent selectivity over other reactive oxygen species. More attractively, the target responsive fluorescent color change of EuPS@AnC/ZIF-8 allowed 1O2 to be easily identified by the naked eye under a UV lamp. We hope that this study will provide a new insight into the design and application of multifunctional composites based on metal-organic frameworks.


[Pain management of elderly in nursing homes].
The aim of this study was to determine pain management status of the elderly in nursing homes. The descriptive study sample included 82 elderly who presented to two nursing homes in İzmir between February-July 2012. In this study, Elderly Identification Form, Mini-Mental Scale, McGill Pain Scale (MAS) and Pain Management Inventory were used as the data collection tool. It was determined that the highest rates of complaints the elderly individuals had were knee pain (64.6%) and headache (58.5%) in this study. Of the elderly people participating in the study, 96.3% took pain relievers for pain management and according to their statements, of the pain management methods they used, resting and directing attention to something else (X=5.76±0.87) and taking prescribed pain relievers (X=5.69±0.87) were very beneficial. In elderly individuals, it is important to use pharmacological and non-pharmacological methods for pain management. Therefore, it is recommended to determine the most frequently used methods for pain management by the elderly and to integrate them into the care plan.


Mitochondrial DNA of Anisakis simplex s.s. as a potential tool for differentiating populations.
Anisakis simplex s.s. specimens from Gadus morhua, Gadus ogac, Reinhardtius hippoglossoides, Clupea harengus, Micromesistius poutassou, Pleurogrammus monopterygius, and Oncorhynchus nerka, caught in the north Atlantic and Pacific, were examined. Identity of the parasite species was confirmed using a molecular key. All specimens were used for amplifying a part of the non-coding sequence of the AT-rich region, flanked by the nad6-nad4L-trnW-trnE-rrnS-trnS2, and trnN-trnY-nad1 genes. This part of the mtDNA was chosen as a promising fragment, which could yield information regarding population differentiation. The number of samples and their geographical origin was sufficient to compare the 2 regions. The Bayesian analysis provided strong support for a population split into 2 groups, one representing A. simplex s.s. samples from the Pacific, and the other representing all the Atlantic samples. It is highly probable that observed subpopulations were constituted after the connection between the Atlantic and Pacific had been closed and movement between these 2 oceans was prevented.


Individual Treatment Effect Estimation of 2 Doses of Dabigatran on Stroke and Major Bleeding in Atrial Fibrillation.
We aimed to estimate absolute benefit and harm from treatment with dabigatran in individual patients with atrial fibrillation, and to select the optimal dose for each individual. We derived and validated a prediction model for ischemic stroke/systemic embolism and major bleeding in patients with atrial fibrillation from the 3 treatment arms of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy With Dabigatran Etexilate) (n=11 955 in derivation cohort, n=6158 in validation cohort). Readily available patient characteristics were included in Fine and Gray competing risk models (sex, age, smoking, antiplatelet drugs, previous vascular disease, diabetes mellitus, blood pressure, estimated glomerular filtration rate, and hemoglobin). Five-year risks for ischemic stroke/systemic embolism and major bleeding were estimated without anticoagulation therapy, and compared with high- and low-dose dabigatran. Model calibration was good, and discrimination was adequate with a c-statistic of 0.65 (95% CI, 0.62-0.70) for ischemic stroke/systemic embolism and 0.69 (95% CI, 0.66-0.71) for major bleeding. The 5-year absolute risk reduction for ischemic stroke/systemic embolism with dabigatran 150 mg twice daily ranged from <10% in 20% of patients to >25% in 14% of patients, and the 5-year absolute risk increase for major bleeding ranged from <5% in 53% of patients to 15% to 20% in 1% of patients. Comparing high-dose to low-dose dabigatran, the net benefit (absolute risk reduction minus absolute risk increase) was positive for 46% of patients. The absolute treatment benefits and harms of dabigatran in atrial fibrillation can be estimated based on readily available patient characteristics. Such treatment effect estimations can be used for shared decision making before starting dabigatran treatment and to determine the optimal dose. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00262600.


Randomized study of online vaccine reminders in adult primary care.
Online immunization reminders were implemented in an adult medicine setting in which all immunization history, vaccine ordering and charting were required online. Physicians were randomized to one of two arms in a cross-over design. Each arm was shown online recommendations for vaccines indicated by nationally accepted guidelines either during the first or during the second part of the study period. The main purpose of the study was to assess the impact of reminders on correct decisions related to prescribing vaccines. Online reminders had the following impact on physician behavior: 1) Physicians used the application almost 3 times as often when shown reminders. 2) Physicians in the reminder group were 27% less likely to order a vaccine in the reminder group (P- value 0.0005). 3) Compliance with guidelines was improved significantly for Tetanus and for Hepatitis B in several analyses. No such effects were found for Pneumoccocal, Measles, or Influenza vaccines.


Pre-Anaesthetic Assessment Of Intracranial Pressure Using Optic Nerve Sheath Diameter In Patients Scheduled For Elective Tumour Craniotomy.
The objective of study was to determine the pre-anaesthetic status of intracranial pressure (ICP), using ultrasonographic measurement of optic nerve sheath diameter (ONSD) inpatient scheduled for elective tumour craniotomy. The secondary objective was to compare the diagnostic accuracy of ONSD guided rise in ICP with clinical and radiographic parameters. This is prospective observational study, conducted at single neurosurgical theatre of The Aga Khan University over a period of one year. After getting ethical approval and informed consent patient fulfilling inclusion criteria and planned for elective tumour craniotomy were enrolled in study. The clinical and radiographic signs predicting the status of ICP were recorded. The ultrasonographic measurement of ONSD was done using liner array probe. Value more than 5 mm was considered as abnormal. Total 26 cases were enrolled. Seventy percent patients showed rise in ICP based on clinical parameters, while 65% diagnosed to have raised ICP on the basis of radiographic findings. The ultrasonographic measurement of ONSD predicted this rise in 61% of cases. The diagnostic accuracy of ONSD in detecting raised ICP in comparison to clinical and radiographic evidence was 87.5% respectively. The ultrasonographic-guided ONSD was used successfully for predicting the status of ICP in pre-induction phase of anaesthesia. It also showed good correlation in diagnosing rise in ICP as compared to clinical and radiographic parameters, which indicates that test can be used reliably in preoperative period for patients planned for tumour craniotomy.


Psychophysical evidence of a sustained input to directionally selective motion mechanisms.
Human psychophysical evidence congruent with neurophysiological findings of a sustained input to directionally selective motion sensors in cat visual cortex is reported. Apparent motion was produced by displaying a group of dots in two frames (F1 and F2), where F2 was a translated version of F1. All stimulus sequences included a period during which F1 and F2 were displayed concurrently (combined images) and a period during which only F1 or F2 was on display (single images). There were three stimulus sequences: a display beginning with combined and ending with single image, a display beginning with single and ending with combined image, and a display beginning with F1, continuing with combined image, and ending with F2. Six durations of single and of combined images (10, 20, 40, 80, 160, and 320 ms) were crossed factorially in each stimulus sequence. Directional motion was seen easily at long durations of the single image in all stimulus sequences, as would be expected on the basis of a sustained input to the directional-motion-sensing mechanisms. Perception of directional motion improved with the duration of single images, but declined as the duration of combined images was increased. Baker and Cynader's model could account for the effect of duration of single images, but not for the effect of duration of combined images. An elaborated version of the model provides a good qualitative match to all empirical findings.


PMHS impact response in 3 m/s and 8 m/s nearside impacts with abdomen offset.
Lateral impact tests were performed using seven male post-mortem human subjects (PMHS) to characterize the force-deflection response of contacted body regions, including the lower abdomen. All tests were performed using a dual-sled, side-impact test facility. A segmented impactor was mounted on a sled that was pneumatically accelerated into a second, initially stationary sled on which a subject was seated facing perpendicular to the direction of impact. Positions of impactor segments were adjusted for each subject so that forces applied to different anatomic regions, including thorax, abdomen, greater trochanter, iliac wing, and thigh, could be independently measured on each PMHS. The impactor contact surfaces were located in the same vertical plane, except that the abdomen plate was offset 5.1 cm towards the subject. The masses of the sleds and the force- deflection characteristics of the energy-absorbing interface material between the sleds were set to provide the impactor sled with a velocity profile that matched the average driver door velocity history produced in a series of side NCAP tests. Impactor padding was also selected so that average ATD pelvis and thorax responses from the same series of side NCAP tests were reproduced when the ATD used in these tests was impacted using the average door-velocity history. Each subject was first impacted on one side of the body using an initial impactor speed of 3 m/s. If a post-test CT scan and strain-gage data revealed two or fewer non-displaced rib fractures, then the PMHS was impacted on the contralateral side of the body at a speed of 8 m/s or 10 m/s. The results of tests in the 3 m/s and 8 m/s conditions were used to develop force-deflection response corridors for the abdomen, force history response corridors for the pelvis (iliac wing and greater trochanter), the midthigh, and the thorax. Response corridors for the lateral acceleration of the pelvis were also developed. Future work will compare side impact ATD responses to these response corridors.


Chitosan (biochikol 020 PC) in the control of some ornamental foliage diseases.
Chitosan, (Biochikol 020 PC) a potential elicitor of plant defence and also an active inhibitor of fungal growth was used in experiments. The compound was used at concentrations 0.01 to 0.2% as a plant spray for rose protection against Sphaerotheca pannosa var. rosae, Peronospora sparsa and Diplocarpon rosae, Oidium chrysanthemi and Puccinia horiana on chrysanthemum, against Melampsora epitea on willow. Myrothecium roridum on dieffenbachia and against Lophodermium spp on Scots pine. Effectiveness of this product, applied curatively 2-times at 7-day-intervals after appearance of rose powdery mildew symptoms on most of plant parts, was about 32%. When compound was applied just after the first disease symptoms appearance, after 2-week-protection its effectiveness was about 43-60%. After 4 weeks, effectiveness of chitosan (Biochikol 020 PC) increased and ranged from 67 to 77%. In the control of P. sparsa on rose shrubs, growing in plastic tunnel, chitosan at conc. 0.025% was applied 4 times at weekly intervals. Effectiveness of chitosan against this pathogen was over 72%, similar as standard fungicide. Increase of chitosan (Biochikol 020 PC) concentration resulted in decrease of its effectiveness. In case of D. rosae control, chitosan used 9 times at weekly intervals was applied after first disease symptoms. After 3-week-protection effectiveness of the compound varied from 18 to 60% according to used concentration. After 9 weeks of protection effectiveness of tested product ranged from 16 to 23% and was connected with used concentration. Increase of chitosan concentration resulted in better protection of rose shrubs. Effectiveness of chitosan (Biochikol 020 PC) used 4-times at conc. 0.01 to 0.05% as chrysanthemum spray in the control of Oidium chrysanthemi ranged from 69 to 79%, whereas against Puccinia horiana from 54-97%. Two-time-spraying of willow with rust symptoms (Melampsora epitea) with chitosan at conc. 01-0.04% caused decrease of disease severity from 26 to 47%. Additionally about 10 to 25% of uredinia were dried up. Chitosan (Biochikol 020 PC) applied for leaf spraying inhibited the development of Myrothecium leaf spot on dieffenbachia more than 85%. Curative application of the compound controlled Myrotecium leaf spot at about 40%. Chitosan efficacy was also tested against one-year-old Pinus sylvestris seedlings growing in field conditions. Plants were sprayed fortnightly 14-times (long programme) or 5-times (short programme) against Lophodermium spp. Observations made during next spring showed that effectiveness of chitosan (Biochikol 020 PC) was more than 50% (long programme) and below 50% (short programme).


Alcohol inhibits cell-cell adhesion mediated by human L1.
Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. L1-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited L1-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. L1-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit L1-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of L1-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of L1-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders.


A novel administrative structure supporting academic nursing practice-based scholarship.
Practice-based scholarship (PBS) is critical for advancing nursing science, and for changing and saving lives. The purpose of this paper is to share two major initiatives implemented at a Midwest College of Nursing (CON) to improve support for PBS. The CON's Office of Research and Scholarship and Office of Faculty Practice were strategically redesigned to integrate and support practice scholarship across the CON. We share this example as a call to action and blueprint for other schools interested in elevating and advancing PBS.


Predicting the effects of ocean acidification on predator-prey interactions: a conceptual framework based on coastal molluscs.
The influence of environmental change on species interactions will affect population dynamics and community structure in the future, but our current understanding of the outcomes of species interactions in a high-CO2 world is limited. Here, we draw upon emerging experimental research examining the effects of ocean acidification on coastal molluscs to provide hypotheses of the potential impacts of high-CO2 on predator-prey interactions. Coastal molluscs, such as oysters, mussels, and snails, allocate energy among defenses, growth, and reproduction. Ocean acidification increases the energetic costs of physiological processes such as acid-base regulation and calcification. Impacted molluscs can display complex and divergent patterns of energy allocation to defenses and growth that may influence predator-prey interactions; these include changes in shell properties, body size, tissue mass, immune function, or reproductive output. Ocean acidification has also been shown to induce complex changes in chemoreception, behavior, and inducible defenses, including altered cue detection and predator avoidance behaviors. Each of these responses may ultimately alter the susceptibility of coastal molluscs to predation through effects on predator handling time, satiation, and search time. While many of these effects may manifest as increases in per capita predation rates on coastal molluscs, the ultimate outcome of predator-prey interactions will also depend on how ocean acidification affects the specified predators, which also exhibit complex responses to ocean acidification. Changes in predator-prey interactions could have profound and unexplored consequences for the population dynamics of coastal molluscs in a high-CO2 ocean.


Transfer of knowledge into clinical practice: an ongoing problem. An example of adverse drug reactions impairing male fertility.
There is still a gap between the information available on the desired and adverse effects of drugs, and the use of these drugs in clinical practice. We present an enquiry from a patient with a wish to father a child. He asked if carbamazepine and/or lercanidipine might be the cause of his raised prolactin level; his urologist had denied this. After searching the literature, we found that both drugs possibly raise prolactin levels and, in addition, may have negative effects on spermatogenesis, male fertility hormones and the fertilisation process. The patient was recommended to discuss the medication with his neurologist and cardiologist and, if possible, change or discontinue both drugs. An extensive search was necessary to gather the relevant information. In this case relevant data about the drugs' effects on male fertility were available, but difficult to obtain.


Research priorities in occupational health in Italy.
To find a broad consensus on research priorities and strategies in the field of occupational health and safety in Italy. A two phase questionnaire survey was based on the Delphi technique previously described in other reports. 310 Occupational safety and health specialists (from universities and local health units) were given an open questionnaire (to identify three priority research areas). The data obtained from respondents (175, 56.4%) were then used to draw up a list of 27 priority topics grouped together into five macrosectors. Each of these was given a score ranging from 1 (of little importance) to 5 (extremely important). With the mean scores obtained from a total of 203 respondents (65.4%), it was possible to place the 27 topics in rank order according to a scale of priorities. Among the macrosectors, first place was given to the question of methodological approach to research in this field, and for individual topics, occupational carcinogenesis and quality in occupational medicine were ranked first and second, respectively. The question of exposure to low doses of environmental pollutants and multiple exposures ranked third among the priorities; the development of adequate and effective approaches and methods for worker education and participation in prevention was also perceived as being an important issue (fourth place). This study (the first of its kind in Italy) enabled us to achieve an adequate degree of consensus on research priorities related to the protection of occupational health and safety. Disparities in the mean scores of some of the issues identified overall as being research priorities, seem to be linked both to geographical area and to whether respondents worked in local health units or universities. This finding requires debate and further analysis.


Food-borne Botulism Caused by Clay Cheese: A Case Report.
Recently, the use of metal and plastic containers instead of clay containers in producing this type of cheese has provided the anaerobic condition for growing the bacterium and producing the botulinum toxin. In this case report was to introduce "clay cheese dug in the ground" as a source of botulinum toxin for the first time. A 34-year-old man with dizziness, asthma, and inability to swallow for four days referred to the hospital emergency department. He had diplopia and ptosis for two days. During admission to the emergency, the patient was conscious without fever, but with dysarthria and bilateral ptosis, an impaired gag reflex, slow right papillary reaction to light, a decreased eye movement, and a decreased power of facial muscles and limbs. The patient reported the use of clay cheese in a week before referring to the emergency. Hematological, biochemical, electrocardiogram, magnetic resonance imaging, and chest X-ray assays were normal. According to the Centers for Disease Control and Prevention classification, these symptoms were related to botulism. The evaluation of serum samples, emission, and gastric juice confirmed botulism by type A toxin. Considering the clinical results of this case study, clay cheese, which is produced in the west of Iran, can be introduced as a new source of the botulinum toxin.


Computing the optimal path in stochastic dynamical systems.
In stochastic systems, one is often interested in finding the optimal path that maximizes the probability of escape from a metastable state or of switching between metastable states. Even for simple systems, it may be impossible to find an analytic form of the optimal path, and in high-dimensional systems, this is almost always the case. In this article, we formulate a constructive methodology that is used to compute the optimal path numerically. The method utilizes finite-time Lyapunov exponents, statistical selection criteria, and a Newton-based iterative minimizing scheme. The method is applied to four examples. The first example is a two-dimensional system that describes a single population with internal noise. This model has an analytical solution for the optimal path. The numerical solution found using our computational method agrees well with the analytical result. The second example is a more complicated four-dimensional system where our numerical method must be used to find the optimal path. The third example, although a seemingly simple two-dimensional system, demonstrates the success of our method in finding the optimal path where other numerical methods are known to fail. In the fourth example, the optimal path lies in six-dimensional space and demonstrates the power of our method in computing paths in higher-dimensional spaces.


Daily sodium intake influences the relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism and hypertension in older adults.
The angiotensin-converting enzyme insertion/deletion (I/D) gene polymorphism has been widely reported as being associated with hypertension; however, most studies do not consider environmental/behavioral factors. This study aimed to investigate the relationship among angiotensin-converting enzyme insertion/deletion gene polymorphism, environmental/behavioral factors, and hypertension in community-dwelling elderly individuals. All community-dwelling older adults from Aiquara, Bahia, Brazil, were invited to take part in this study. After exclusions, 234 elderly participants were submitted to a data collection, which included sociodemographics, lifestyle and health status questionnaires, clinical assessment, and blood withdrawal. From the blood samples, the gene polymorphism was identified through polymerase chain reaction and patients grouped as II or D allele carriers (ID and DD genotypes). Hypertension was defined by self-report of the condition and confirmed by antihypertensive drug treatment. Chi-square test was used to identify differences in the proportions distributed between groups of each dependent variable (ie, genotype, diagnosis of hypertension, and blood pressure state from medicated patients with hypertension). The prevalence of hypertension was 59.3% and was associated with diabetes mellitus and obesity, but not with angiotensin-converting enzyme insertion/deletion gene polymorphism. However, carriers of the II genotype, a salt-sensitivity genotype, exhibited a significantly greater estimated sodium intake. In addition, among medicated elderly patients with hypertension, II genotype carriers exhibited poor blood pressure control, despite similar antihypertensive drug treatment in D allele carriers, while exhibiting a greater estimated sodium intake. Our results provide new evidence regarding the interaction of genetic and environmental/behavioral factors in the genesis of hypertension among elderly patients, as well as in blood pressure control in medicated elderly patients with hypertension.


Quantum Simulation of the Bosonic Creutz Ladder with a Parametric Cavity.
There has been a growing interest in realizing quantum simulators for physical systems where perturbative methods are ineffective. The scalability and flexibility of circuit quantum electrodynamics make it a promising platform for implementing various types of simulators, including lattice models of strongly coupled field theories. Here, we use a multimode superconducting parametric cavity as a hardware-efficient analog quantum simulator, realizing a lattice in synthetic dimensions with complex hopping interactions. The coupling graph, i.e., the realized model, can be programmed in situ. The complex-valued hopping interaction further allows us to simulate, for instance, gauge potentials and topological models. As a demonstration, we simulate a plaquette of the bosonic Creutz ladder. We characterize the lattice with scattering measurements, reconstructing the experimental Hamiltonian and observing important precursors of topological features including nonreciprocal transport and Aharonov-Bohm caging. This platform can be easily extended to larger lattices and different models involving other interactions.


Uncertainty in the minimum event risk to justify treatment was evaluated.
To derive expressions for the standard errors (SEs) and coefficients of variation (CV) of the threshold number needed to treat (NNT(t)) and the minimum target event risk for treatment (MERT). NNT(t) reflects the point at which the risks and costs of a clinical intervention balance the benefit. MERT defines the minimum target event risk at which the intervention is justified. Uncertainty in these measures has not previously been investigated. SEs for NNT(t) and MERT were derived. The corresponding CVs are particularly useful, because they decompose the variability of NNT(t) and MERT into the uncertainty in their components (the values of target and adverse events, and the adverse event risk [AER]). The precision required for these components to formulate treatment recommendations is, thereby, highlighted. These ideas were illustrated with data concerning warfarin treatment for atrial fibrillation. Our expressions for uncertainty in NNT(t) and MERT inform the confidence one has in initiating a clinical intervention. In our example, a recommendation for treatment could be made for groups of patients whose risk exceeded the range of uncertainty in MERT. However, for lower-risk patients, a recommendation for or against treatment could not be made, mainly because of the limited data on AERs. Our methods can also be used to estimate how much additional data would be required to provide a firmer recommendation for such patient groups.


Impact of Uric Acid on Hypertension Occurrence and Target Organ Damage: Insights From the STANISLAS Cohort With a 20-Year Follow-up.
Recent studies have shown that hyperuricemia may be associated with incident hypertension (HTN). We examined whether serum uric acid (SUA) is a predictor of HTN and target organ damage (TOD) 20 years later in initially healthy middle-aged individuals. Participants from the Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) a single-center familial longitudinal cohort study (961 initially healthy adults and 570 children) underwent clinical and laboratory measurements at baseline and after approximately 20 years. Blood pressure (BP: using ambulatory BP measurements), urine albumin-to-creatinine ratio, estimated glomerular filtration rate (eGFR), left ventricular hypertrophy (LVH), diastolic dysfunction, and carotid-femoral pulse wave velocity (PWV) were measured at the end of follow-up. In the parent population, higher baseline or last SUA levels and higher change in SUA (ΔUA) were significantly associated with an increased risk of HTN development, even after adjusting for known HTN risk factors (all P < 0.01). Higher baseline SUA was marginally associated with an increased risk of having high carotid-femoral PWV (P = 0.05). The association of SUA with BP increase was body mass index dependent (the increase in BP being greater in leaner subjects; interactionp < 0.05), and the association of SUA with eGFR decline was age dependent (the decline in eGFR being greater in older subjects; interactionp < 0.05). There was no significant association between SUA and diastolic dysfunction or LVH. In the whole population (i.e. including children), a significant association between SUA at baseline and the risk of HTN and higher carotid-femoral PWV was also found (both P < 0.02). Increased SUA is associated with the development of HTN and vascular/renal TOD in initially healthy midlife subjects.


Periodontal muco-adhesive formulations for the treatment of infectious periodontal diseases.
Extensive efforts have recently been focused on targeting a drug or delivery system in a particular region of the body for extended period of time, not only for local targeting of drugs but also for the better control of systemic drug delivery. The concept of periodontal drug delivery systems has fascinated many investigators to the possible use of various polymers, which can overcome various physiological barriers in long-term drug delivery, there by rendering the treatment more effective and safe for local disorders and systemic problems. Presence of a smooth and relatively immobile surface for placement of a bio-adhesive dosage form has made periodontal route more suitable for sustained delivery of therapeutic agents using bio-adhesive systems. Antibiotics, antiseptics and other poorly absorbable drugs can be successfully delivered via periodontium for the treatment of infectious periodontal diseases. The dosage forms include microparticles, microspheres, adhesive gels, adhesive films, adhesive creams and ointments. Bio-adhesive periodontal drug delivery system can also exert positive influence on drug effectiveness by keeping the drug in the region proximal to its absorption window and allow the targeting and localization of the drug at the specific site.


In vivo evidence for transdifferentiation of peripheral neurons.
It is commonly thought that differentiated neurons do not give rise to new cells, severely limiting the potential for regeneration and repair of the mature nervous system. However, we have identified cells in zebrafish larvae that first differentiate into dorsal root ganglia sensory neurons but later acquire a sympathetic neuron phenotype. These transdifferentiating neurons are present in wild-type zebrafish. However, they are increased in number in larvae that have a mutant voltage-gated sodium channel gene, scn8aa. Sodium channel knock-down promotes migration of differentiated sensory neurons away from the ganglia. Once in a new environment, sensory neurons transdifferentiate regardless of sodium channel expression. These findings reveal an unsuspected plasticity in differentiated neurons that points to new strategies for treatment of nervous system disease.


Transition to adult mental health services for young people with attention deficit/hyperactivity disorder (ADHD): a qualitative analysis of their experiences.
There is little research on the process of transition between child and adolescent mental health services (CAMHS) and adult mental health services (AMHS). More recently, there is growing recognition that Attention Deficit/Hyperactivity Disorder (ADHD) may persist into adulthood requiring services beyond age 18. However, despite National Institute for Health and Clinical Excellence (NICE) Guidance which recommends specialist services for adults with ADHD, there is currently a lack of such services in the UK. The aim of the current study is to explore the experiences of young people with ADHD during transition from CAMHS to AMHS. Semi-structured qualitative interviews with ADHD patients accessing CAMHS clinics in Nottinghamshire were analysed using thematic analysis. Ten semi-structured interviews were transcribed and analysed. We found that patients' relationships with their clinician were a key factor in both their reported experience of CAMHS and the transition process. Perceived responsibility of care was also pivotal in how the transition process was viewed. Nature and severity of problems and patients expectations of adult services were also contributing factors in the transition process. The need for continued parental support was openly accepted and thought to be required by the majority of young people with ADHD during transition. Timely preparation, joint working, good clinician relationships and parental support serve to facilitate the process of transition for young people with ADHD. Nature and severity of problems are perceived to impede or facilitate transition, with predominantly more 'complex presentations' with associated mental health problems more familiar to AMHS (e.g. self-harm, depression) making for smoother transitions to adult services. Transitions to AMHS were more difficult when ADHD was viewed as the main or sole clinical problem. Further exploration of young people's experiences of transition and their engagement with and experience of adult services is required to provide an overall picture of facilitators to successful transition and integration into adult services.


Recent Advances in Manufacturing Innovative Stents.
Cardiovascular diseases are the most distributed cause of death worldwide. Stenting of arteries as a percutaneous transluminal angioplasty procedure became a promising minimally invasive therapy based on re-opening narrowed arteries by stent insertion. In order to improve and optimize this method, many research groups are focusing on designing new or improving existent stents. Since the beginning of the stent development in 1986, starting with bare-metal stents (BMS), these devices have been continuously enhanced by applying new materials, developing stent coatings based on inorganic and organic compounds including drugs, nanoparticles or biological components such as genes and cells, as well as adapting stent designs with different fabrication technologies. Drug eluting stents (DES) have been developed to overcome the main shortcomings of BMS or coated stents. Coatings are mainly applied to control biocompatibility, degradation rate, protein adsorption, and allow adequate endothelialization in order to ensure better clinical outcome of BMS, reducing restenosis and thrombosis. As coating materials (i) organic polymers: polyurethanes, poly(ε-caprolactone), styrene-b-isobutylene-b-styrene, polyhydroxybutyrates, poly(lactide-co-glycolide), and phosphoryl choline; (ii) biological components: vascular endothelial growth factor (VEGF) and anti-CD34 antibody and (iii) inorganic coatings: noble metals, wide class of oxides, nitrides, silicide and carbide, hydroxyapatite, diamond-like carbon, and others are used. DES were developed to reduce the tissue hyperplasia and in-stent restenosis utilizing antiproliferative substances like paclitaxel, limus (siro-, zotaro-, evero-, bio-, amphi-, tacro-limus), ABT-578, tyrphostin AGL-2043, genes, etc. The innovative solutions aim at overcoming the main limitations of the stent technology, such as in-stent restenosis and stent thrombosis, while maintaining the prime requirements on biocompatibility, biodegradability, and mechanical behavior. This paper provides an overview of the existing stent types, their functionality, materials, and manufacturing conditions demonstrating the still huge potential for the development of promising stent solutions.


[Stress fractures in athletes. role of magnetic resonance imaging in predicting injury morbidity].
Magnetic resonance imaging is a useful tool for stress fractures (SF) diagnosis, allowing the estimation of injury severity. The aim of this study was to determine the relation between the severity of SF in athletes determined by magnetic resonance imaging and the morbidity estimated as the time to return to sport. Thirty-four cases of stress fractures, (29 athletes; 12 female, 17 male; age 26.3 +/- 12.5), were studied by radiographs and magnetic resonance imaging. Injuries were classified according to Arendt's scale and they were analyzed according to site, activity level, delay in diagnosis and time needed to return to sports. The tibia was the most affected bone (n=12; 35.2%), followed by the tarsal navicular (n=5; 14.7%), and the metatarsals (n=4; 11.7%). Injury severity according to magnetic resonance imaging appearance was: grade 1=14.7%; grade 2=14.7%; grade 3=38.2%; grade 4=32.4%. The main finding was the positive significant correlation between injury severity and recovery time (r=0.66, p=0.0002). In conclusion, significant correlation exists between stress fracture injury severity determined by magnetic resonance image and recovery time in athletes. The use of a systematic graded magnetic resonance image evaluation may assist the physician to define clinical management, supervise the rehabilitation program and estimate the return to sport activity.


Antenatal diagnosis of lethal skeletal dysplasias.
Lethal skeletal dysplasias (LSD) are a heterogeneous group of rare but important genetic disorders characterized by abnormal growth and development of bone and cartilage. We describe the diagnosis and outcome of 29 cases of lethal skeletal dysplasias evaluated between January 1989 and December 1996 at the University of Maryland Medical Center and the Ultrasound Institute of Baltimore. Two cases presented at delivery with no prenatal care while the remaining 27 cases were identified by antenatal sonography. Final diagnoses included thanatophoric dysplasia (14), osteogenesis imperfecta, type II (6), achondrogenesis (2), short rib syndromes (3), campomelic syndrome (2), atelosteogenesis (1), and no evidence of a skeletal dysplasia (1). Twenty out of 27 pregnancies were terminated with an average at detection of 21.6 weeks. The other 7 pregnancies that went on to deliver had an average age at detection of 29.2 weeks. Fetal abnormalities in the terminated pregnancies were identified at a significantly earlier gestational age (P = 0.0016) than the pregnancies that continued. While the identification of LSD by sonography was excellent (26/27), only 13/27 (48%) were given an accurate specific antenatal diagnosis. In 8/14 (57%) cases with an inaccurate or nonspecific diagnosis there was a significant or crucial change in the genetic counseling. Thus, while antenatal sonography is an excellent method for discovering LSD, clinical examination, radiographs, and autopsy are mandatory for making a specific diagnosis.


Long-term potentiation at single fiber inputs to hippocampal CA1 pyramidal cells.
Despite extensive investigation, it remains unclear whether presynaptic and/or postsynaptic modifications are primarily responsible for the expression of long-term potentiation (LTP) in the CA1 region of the hippocampus. Here we address this issue by using techniques that maximize the likelihood of stimulating a single axon and thereby presumably a single synapse before and after the induction of LTP. Several basic properties of synaptic transmission were examined including the probability of neurotransmitter release (Pr), the quantal size (q), and the so-called potency, which is defined as the average size of the synaptic response when release of transmitter does occur. LTP was routinely associated with an increase in potency, whereas increases in Pr alone were not observed. LTP was also reliably induced when baseline Pr was high, indicating that synapses with high Pr can express LTP. These results suggest that the mechanism for the expression of LTP involves an increase in q and is difficult to explain by an increase in Pr alone.