Adherence to surgical hand rubbing directives in a hospital district of Southwest Finland.
The primary objective was to measure the compliance with alcohol-based surgical hand rubbing (SHR) among operation room personnel. The secondary objective was to evaluate the effect of feedback sessions on compliance. This was a prospective observational before-after intervention study. Between October 2010 and June 2012 the hygiene nurses observed SHR among operation room personnel in the hospital district of Southwest Finland. After feedback sessions a second observation round was conducted in the main operation room of Turku University Hospital. The first observation round comprised 477 observations: 259 (54%) were doctors, 190 (40%) nurses and 28 (5%) other personnel. In the second observation round a total of 210 observations were made. During the first round in 42% of observations the 3 min SHR time recommended by WHO was used. Median times for SHR were 1 min 50 s (range 0 min to 5 min 44 s) for doctors and 3 min 25 s (range 1 min 1 s to 8 min 15 s) for nurses, respectively (p < 0.0001). In 40% of observations hands were not properly dried after a wash before applying SHR and in 45% hands were not allowed to dry properly after SHR before donning surgical gloves. After feedback, time for SHR did not significantly improve but technique did. SHR was performed incorrectly in most observations even after feedback. The results stress the importance of more effective education, helping techniques and positive role models for operation room personnel to promote SHR.


Risk stratification and cost-effectiveness analysis of adult patients receiving extracorporeal membrane oxygenation.
A more effective allocation of critical care resources is important as the cost of intensive care increases. A model has been developed to predict the probability of in-hospital death among patients who received extracorporeal membrane oxygenation (ECMO). Cost-effectiveness analyses (CEA) were performed regarding the relationship between hospitalization expenses and predicted survival outcomes. Adult patients who received ECMO in a medical center in Taiwan (2005-2016) were included. A logistic regression model was applied to a spectrum of clinical measures obtained before and during ECMO institutions to identify the risk variables for in-hospital mortality. CEA were reported as a predictive risk in quintiles and defined as the cost of each quality-adjusted life-year (QALY). The distribution of the cost-effectiveness ratio (CER) was measured by the ellipse and acceptability curve methods. A total of 919 patients (659 males, mean age: 53.7 years) were enrolled. Ten variables emerged as significant predictors of in-hospital death. The area under the receiver operating characteristic curve was 0.75 (95% confidence interval: 0.72-0.79). In-hospital and total follow-up times were 40,366 and 660,205 person-days, respectively. The total in-hospital expense was $31,818,701 USD and the total effectiveness was 1687.3 QALY. For the lowest to the highest risk quintile, the mean mortality risks were 0.30, 0.48, 0.61, 0.75, and 0.88, and mean adjusted CER were $24,230, $43,042, $54,929, $84,973, and $149,095 per QALY, respectively. The efficient allocation of limited and costly resources is most important when one is forced to decide between groups of critically ill patients. The current analyses of ECMO outcomes should assist in identifying candidates with the greatest prospect for survival while avoiding futile treatments.


[The comparative analysis of acute poisoning characteristics between cities and rural areas in Guangxi].
To compare the acute-poisoning characteristics between city and rural areas of Guangxi Province in order to provide clinical data for the formation of treatment strategies of acute poisoning in Guangxi. Data of acute poisoning patients as treated in 36 municipal and 12 county hospitals, and also 15 rural clinics in 11 cities of Guangxi during 2005 to 2009 were collected and analyzed according to poisoning population, poisoning site, poisoning process, and poisoning degree. By analysing 3678 and 2153 cases of acute poisoning patients in rural and urban areas, the gender [χ (2) = 5.53, P < 0.05], age [χ (2) = 21.04, P < 0.01], professions [χ (2) = 3156.83, P < 0.01], poisoning site [χ (2) = 429.26, P < 0.01], poisoning cause [χ (2) = 363.06, P < 0.01], poison variety [χ (2) = 1713.12, P < 0.01], poisoning degree [χ (2) = 35.25, P < 0.01] were shown to be significantly different between rural and urban areas. In the rural areas, poisoning occurred predominantly in male (48.10% vs. 44.91%), age between 20-60 years (69.39% vs. 67.53%) and over 61 years old (11.17% vs. 8.69%), farmers by occupation (74.84% vs. 2.79%), home (80.64% vs. 78.07%), sites of labor (11.83% vs. 3.07%) and other sites (4.08% vs. 2.97%), and the chief causes were professional (3.10% vs. 1.30%), taken by mistake (21.85% vs. 20.91%), homicide (0.30% vs. 0.28%), and suicide (39.07% vs. 18.77%), and by pesticide (60.94% vs. 12.13%), plant (7.08% vs. 2.88%) and animal poisons (7.73% vs. 6.56%), belonging to severe poisoning (25.86% vs. 19.04%) were higher than those in town. In the town, poisoning occurred predominantly in female (55.09% vs. 51.90%), age below 19 years old (23.78% vs. 19.44%), unemployed (33.35% vs. 13.76%), student (17.53% vs. 8.43%), industrial workers (31.95% vs. 2.69%), executives (10.84% vs. 0.22%) and other professional (3.53% vs. 0.05%); occurred in schools (8.78% vs. 0.82%), restaurants (5.48% vs. 1.55%), place of entertainment (1.63% vs. 1.09%), by accidental (52.23% vs. 31.27%), therapeutic (4.46% vs. 2.56%), and other reasons (2.04% vs. 1.85%); by chemicals (33.19% vs. 8.55%), medicines (24.31% vs. 9.12%), and other types of poison (20.92% vs. 6.59%); light and medium degree of poisoning (44.87% vs. 41.22%, 36.09% vs. 32.93%) were higher than those in rural areas. Regarding the acute poisoning in Guangxi, the composition of population, the poisoning sites and causes, the types of poisons, the poisoning degree are distinctly different between urban and rural areas.


[Dose distribution of asymmetric fields: comparison of the Helax-TMS with our developed 2D-program ASYMM].
The purpose of this investigation was to compare the commercial 3D-treatment planning system Helax TMS to a simple 2D program ASYMM, concerning the calculation of dose distributions for asymmetric fields. The dose calculation algorithm in Helax-TMS is based on the polyenergetic pencil beam model of Ahnesjö. Our own developed 2D treatment planning program ASYMM, based on the Thomas and Thomas method for asymmetric open fields, has been extended to calculate the dose distributions for open and wedged fields. Using both methods, dose distributions for various asymmetric open and wedged fields of a 4-MV Linear accelerator were calculated and compared with measured data in water. The agreement of the Helax-TMS and the ASYMM with the experiment was good, whereas ASYMM showed a better accuracy for larger asymmetric angles. The explanation for this result is based on the consideration of beam hardening within the flattening filter and edges for different asymmetric settings in ASYMM algorithm. The TMS, however, owns the diverse possibilities that the 3D calculation and corresponding representation provide and holds better application opportunities in clinical routine.


Metal-organic framework derived carbon-confined Ni2P nanocrystals supported on graphene for an efficient oxygen evolution reaction.
Metal-organic framework derived carbon-confined Ni2P nanocrystals supported on graphene with high effective surface area, more exposed active sites, and enhanced charge transport were successfully designed. The resulting material shows excellent oxygen evolution reaction performance with a remarkably low overpotential of 285 mV at 10 mA cm-2 and outstanding durability.


Improving selectivity preserving affinity: new piperidine-4-carboxamide derivatives as effective sigma-1-ligands.
We report the design, synthesis and binding evaluation against σ1 and σ2 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on σ receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward σ1 and σ2 receptors. Very high σ1 affinity (Ki = 3.7 nM) and Kiσ2/Kiσ1 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom.


On the diagnosis and management of neurocutaneous syndrome, a toxicity disorder from dental sealants.
Neurocutaneous syndrome, a newly discovered toxicity disorder, is characterized by neurological sensations, pain, depleted energy, and memory loss as well as itchy cutaneous lesions that may invite various opportunistic infections. Components in the calcium hydroxide dental sealants Dycal, Life and Sealapex have been identified as sources of the observed symptoms. Sulfonamide and neurological toxicity issues are discussed, and three case histories are presented. Additional notes on zinc oxide, Fynal, IRM, and Sultan U/P sealers are also included. Diagnostic and management protocols at the Parasitology Center, Inc., are proposed.


Chimeric TK-NOG mice: a predictive model for cholestatic human liver toxicity.
Due to the substantial interspecies differences in drug metabolism and disposition, drug-induced liver injury (DILI) in humans is often not predicted by studies performed in animal species. For example, a drug (bosentan) used to treat pulmonary artery hypertension caused unexpected cholestatic liver toxicity in humans, which was not predicted by preclinical toxicology studies in multiple animal species. In this study, we demonstrate that NOG mice expressing a thymidine kinase transgene (TK-NOG) with humanized livers have a humanized profile of biliary excretion of a test (cefmetazole) drug, which was shown by an in situ perfusion study to result from interspecies differences in the rate of biliary transport and in liver retention of this drug. We also found that readily detectable cholestatic liver injury develops in TK-NOG mice with humanized livers after 1 week of treatment with bosentan (160, 32, or 6 mg/kg per day by mouth), whereas liver toxicity did not develop in control mice after 1 month of treatment. The laboratory and histologic features of bosentan-induced liver toxicity in humanized mice mirrored that of human subjects. Because DILI has become a significant public health problem, drug safety could be improved if preclinical toxicology studies were performed using humanized TK-NOG.


Pain extent is associated with Central Sensitization Inventory but not widespread pressure pain sensitivity or psychological variables in women with fibromyalgia.
To investigate the relationship between pain extent, as a clinical sign of central sensitization, and clinical, psychological, and pressure sensitivity in women with fibromyalgia syndrome (FMS). In this study, 126 females with FMS completed demographic (age, gender, body mass index, height, weight), clinical (pain history, and pain intensity at rest and during daily living activities), psychological (depression and anxiety levels), and neurophysiological [pressure pain threshold (PPT)] assessments. The Central Sensitization Inventory (CSI) was also used to collect self-reported symptoms of sensitization. Pain extent and frequency maps were obtained from pain drawings using customized software. After conducting a multivariable correlation analysis to determine the relationships between variables, a stepwise linear regression model analysis was performed to identify variables associated with pain extent. Pain extent was positively associated with age (r = 0.17), years with pain (r = 0.27), pain during daily life activities (r = 0.27), and CSI (r = 0.42) (all p < 0.05). The stepwise regression analysis revealed that 27.8% of the pain extent was explained by CSI, age, and years with pain. This study found that larger pain extent was associated with self-reported outcomes, i.e. CSI, but not neurophysiological outcomes, i.e. PPTs, of sensitization in women with FMS. Older age and a longer history with pain symptoms were also associated with larger pain extent.


Development of a MicroStrip Gas Chamber as a Time-Resolved Area Detector.
A two-dimensional microstrip gas chamber (MSGC) has been developed with a 10 cm-square detection area and an ultrafast read-out system. The MSGC was made using multi-chip module (MCM) technology, and has a very thin substrate of 17 micro m and many anodes and back strips, both with 200 micro m pitches. The new read-out system, in which the hit addresses of the electrodes were sequentially encoded to the hit positions by a synchronous clock, handles data rates of up to 10(7) events s(-1) from MSGCs. This enables the acquisition of fast and sequential digital images. Furthermore, since the MSGC is a real photon-counting detector, the timing of the photons, to an accuracy of a few tens of nanoseconds, and energy can be recorded. Here, the performance of the MSGC system as a real-time area detector is reported, and the abilities of this system are discussed.


Meanings, functions, and experiences of living at home for individuals with dementia at the critical point of relocation.
The sociophysical home environment is an integral component of everyday coping, self-identity, and well-being for individuals with dementia; however, residential discontinuity is a common experience for many of these individuals. This article examined the meanings, functions, and experiences associated with living at home for individuals with dementia at the critical point of relocation to a residential care facility. Qualitative research methods were used to analyze in-depth interviews with 16 individuals with dementia at their homes within 2 months prior to relocation. At the time of relocation, living at home had become a paradoxical experience for most participants. The findings inform practice and policy interventions at both individual and societal levels to help individuals with dementia age in place for as long as possible and to maximize their efforts to "place" themselves in their new living environments after relocation.


The impact of watching educational video clips on analogue patients' physiological arousal and information recall.
Investigating the influence of watching three educational patient-provider interactions on analogue patients' emotional arousal and information recall. In 75 analogue patients the emotional arousal was measured with physiological responses (electrodermal activity and heart rate) and self-reported arousal. A moderate increased level of physiological arousal was measured but not too much to inflict emotional distress. Recall of information was within the pursued range. Hence, physiological arousal is not expected to hinder the goals we pursue with our online intervention. Still, developers and researchers should remain attentive to the self-reported (conscious) and hidden (subconscious) emotions evoked by the content of educational video clips presented in self-help interventions. A moderate increased level of arousal is preferred to increase the learning capacity. However, too much arousal may decrease the learning capacity and may cause distress, which should obviously be avoided for ethical reasons.


Growth Factor-Mediated Migration of Bone Marrow Progenitor Cells for Accelerated Scaffold Recruitment.
Tissue engineering approaches using growth factor-functionalized acellular scaffolds to support and guide repair driven by endogenous cells are thought to require a careful balance between cell recruitment and growth factor release kinetics. The objective of this study was to identify a growth factor combination that accelerates progenitor cell migration into self-assembling peptide hydrogels in the context of cartilage defect repair. A novel 3D gel-to-gel migration assay enabled quantification of the chemotactic impact of platelet-derived growth factor-BB (PDGF-BB), heparin-binding insulin-like growth factor-1 (HB-IGF-1), and transforming growth factor-β1 (TGF-β1) on progenitor cells derived from subchondral bovine trabecular bone (bone-marrow progenitor cells, BM-PCs) encapsulated in the peptide hydrogel [KLDL]3. Only the combination of PDGF-BB and TGF-β1 stimulated significant migration of BM-PCs over a 4-day period, measured by confocal microscopy. Both PDGF-BB and TGF-β1 were slowly released from the gel, as measured using their (125)I-labeled forms, and they remained significantly present in the gel at 4 days. In the context of augmenting microfracture surgery for cartilage repair, our strategy of delivering chemotactic and proanabolic growth factors in KLD may provide the necessary local stimulus to help increase defect cellularity, providing more cells to generate repair tissue.


Ectopic expression of ABSCISIC ACID 2/GLUCOSE INSENSITIVE 1 in Arabidopsis promotes seed dormancy and stress tolerance.
Abscisic acid (ABA) is an important phytohormone that plays a critical role in seed development, dormancy, and stress tolerance. 9-cis-Epoxycarotenoid dioxygenase is the key enzyme controlling ABA biosynthesis and stress tolerance. In this study, we investigated the effect of ectopic expression of another ABA biosynthesis gene, ABA2 (or GLUCOSE INSENSITIVE 1 [GIN1]) encoding a short-chain dehydrogenase/reductase in Arabidopsis (Arabidopsis thaliana). We show that ABA2-overexpressing transgenic plants with elevated ABA levels exhibited seed germination delay and more tolerance to salinity than wild type when grown on agar plates and/or in soil. However, the germination delay was abolished in transgenic plants showing ABA levels over 2-fold higher than that of wild type grown on 250 mm NaCl. The data suggest that there are distinct mechanisms underlying ABA-mediated inhibition of seed germination under diverse stress. The ABA-deficient mutant aba2, with a shorter primary root, can be restored to normal root growth by exogenous application of ABA, whereas transgenic plants overexpressing ABA2 showed normal root growth. The data reflect that the basal levels of ABA are essential for maintaining normal primary root elongation. Furthermore, analysis of ABA2 promoter activity with ABA2::beta-glucuronidase transgenic plants revealed that the promoter activity was enhanced by multiple prolonged stresses, such as drought, salinity, cold, and flooding, but not by short-term stress treatments. Coincidently, prolonged drought stress treatment led to the up-regulation of ABA biosynthetic and sugar-related genes. Thus, the data support ABA2 as a late expression gene that might have a fine-tuning function in mediating ABA biosynthesis through primary metabolic changes in response to stress.


Recurrent Multifocal Embolic Strokes in a 50-Year-Old Male: Unmasking Occult Squamous Cell Carcinoma.
Recurrent cryptogenic embolic strokes pose a diagnostic challenge, often necessitating an extensive evaluation to determine the underlying cause. Cancer-related stroke is a frequently overlooked etiology, accounting for a substantial proportion of cryptogenic strokes. This case study underscores the importance of considering occult malignancies in patients with recurrent strokes of unknown origin and emphasizes the need for a comprehensive diagnostic workup to detect hidden malignancies. A 50-year-old male with a complex medical history presented with expressive aphasia and blurred vision resembling previous stroke episodes. Neurological examinations revealed right hemianopsia, paraphasia, and abnormal coordination. Neuroimaging studies showed multiple chronic infarctions, a large hemorrhagic infarction in the left posterior cerebral artery territory, and a small acute-to-subacute left parietal infarction. Due to the time of presentation and the presence of hemorrhagic transformation, the patient did not meet the criteria for intravenous tissue plasminogen activator administration. Given the recurrent nature of the strokes, an extensive evaluation was initiated to determine the underlying cause. Vascular imaging, including magnetic resonance angiography (MRA) of the head and neck and a CT angiogram, showed no significant stenosis. Vasculitis workup and cardiac evaluation yielded negative results. The blood workup was notable for elevated D-dimer levels. The involvement of multiple vascular territories and recurrent stroke despite adequate treatment and the absence of traditional risk factors for stroke raised a high clinical suspicion of occult malignancy. Further investigations led to the diagnosis of locally advanced squamous cell carcinoma (P16+), metastatic to the right neck lymph nodes (cTxN3M0). Although the primary source of cancer could not be identified, the P16+ status suggests the right tonsil or base of the tongue as the probable origin. Anticoagulation therapy was initiated, and the patient was scheduled for chemoradiation therapy. Although routine cancer investigation is not justified in ischemic strokes, the possibility of an occult malignancy should be considered in the presence of multifocal infarctions across different vascular territories with elevated D-dimer levels, particularly when traditional risk factors have been ruled out. A detailed physical exam can help localize the malignancy and early identification of occult malignancies can guide appropriate management strategies and help prevent future strokes. Further clinical trials are needed to establish optimal therapeutic approaches for preventing stroke recurrence in cancer-related strokes.


Management of sexual problems in diabetic patients.
Sexual dysfunction is common in diabetes, with both male and female patients suffering problems with libido, arousal and orgasm. Erectile failure is particularly common and can be treated effectively by pharmacological and mechanical methods. However, psychological and relationship factors may still be important. A comprehensive diabetes care service should routinely offer treatment for sexual dysfunction.


[Genetic analysis and its clinical implication in adult T-cell leukemia/lymphoma].
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis. This disease is caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. Not only viral proteins, such as Tax and HBZ, but also additional genetic and epigenetic aberrations, including gain-of-function alterations in the components of T-cell receptor/NF-κB pathway or deteriorating alterations responsible for immune surveillance, are essential for ATL development and progression. Furthermore, recent investigation has demonstrated the effects of genetic and epigenetic alterations prevalently identified in ATL on the disease phenotype and its clinical outcomes. Aggressive ATL is associated with an increased burden of genetic and epigenetic abnormalities. Higher frequencies of TP53 and IRF4 mutations and several copy number alterations, including PD-L1 amplifications and CDKN2A deletions, are more predominant in aggressive than indolent diseases. In contrast, STAT3 mutations are more frequent in indolent ATL. Several genetic alterations, such as PD-L1 amplification, can predict the clinical outcomes independent of established clinical factors. Therefore, ATL subtypes can further be subdivided into genetically distinct subgroups with different prognoses. The genetic profiling of ATL cases has revealed its molecular pathology and should contribute to improved prognostication and management of patients with ATL.


The roles of estrogen and progesterone in regulating carbohydrate and fat utilization at rest and during exercise.
Compared with men, women use more fat and less carbohydrate to fuel exercise at the same relative intensity. Circulating levels of estrogen and progesterone are likely to play an important role in explaining this gender difference in exercise substrate utilization. Studies, mainly using animal models, have shown that estrogen increases fatty acid availability (lipolysis) and decreases carbohydrate availability and uptake. Studies conducted in humans corroborate the reduction in carbohydrate turnover and oxidation in the presence of estrogen, but the impact on fatty acid availability and utilization is less clear. The effect of circulating estrogen may be mediated, at least in part, by changes in the sensitivity of stored carbohydrate and lipids to mobilization in response to epinephrine. The role of progesterone in metabolic regulation during exercise has not been systematically studied in humans. Understanding the role of the ovarian hormones in fat and carbohydrate metabolism during exercise may have practical applications in terms of understanding the metabolic consequences of amenorrhea, menopause, and hormone replacement therapy (HRT).


Enzymatic Biofuel-Cell-Based Self-Powered Biosensor Integrated with DNA Amplification Strategy for Ultrasensitive Detection of Single-Nucleotide Polymorphism.
Enzymatic biofuel cell (EBFC)-based self-powered biosensors could offer significant advantages: no requirement for an external power source, simple instruments, and easy miniaturization. However, they also suffered from the limitations of lower sensitivity or specific targets. In this study, a self-powered biosensor for the ultrasensitive and selective detection of single nucleotide polymorphisms (SNPs) produced by combining the toehold-mediated strand displacement reaction (SDR) and DNA hybridization chain reaction (HCR) was proposed. Herein, the capture probe (CP) with an external toehold was designed to switch on the sensing system. In the presence of target sequence, both SDR and DNA HCR reaction would happen to produce a long double-helix chain. Because of the electrostatic interaction between [Ru(NH3)6]3+ and the double-helix chain described above, the open circuit voltage ( EOCV) of the as-proposed biosensor was significantly elevated, thus realizing the detection of SNPs. Overall, in this work, an ingeniously constructed self-powered biosensor for the detection of SNPs was created by integrating EBFCs with a DNA amplification strategy. Furthermore, the as-proposed self-powered biosensor not only showed prominent specificity to distinguish the p53 gene fragment from random sequences (e.g., single-base mutant sequences) but exhibited excellent sensitivity with the detection limit of 20 aM. More importantly, the results obtained from the real cell lysate sample have laid a strong foundation for disease diagnostics and, potentially, as a powerful tool for even more fields.


Transcatheter versus surgical aortic valve replacement in patients at low surgical risk: A meta-analysis of randomized trials and propensity score matched observational studies.
Although transcatheter aortic valve replacement (TAVR) is officially indicated for high risk aortic stenosis (AS) patients, the procedure is increasingly being performed in patients who are not at high surgical risk, including a substantial number of low risk patients. However, data on the benefit of TAVR in this patient population is limited. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies with propensity score matching (PSM) of TAVR versus surgical aortic valve replacement (SAVR) in patients who are at low surgical risk. The primary outcome was all-cause mortality. The secondary outcomes included stroke, myocardial infarction, bleeding, and various procedural complications. Six studies (2 RCTs and 4 PSM studies) totaling 3,484 patients were included. Follow-up ranged from 3 months to 3 years (median 2 years). The short-term mortality was similar with either TAVR or SAVR (2.2% for TAVR and 2.6% for SAVR, RR 0.89, 95% CI 0.56-1.41, P = 0.62), however, TAVR was associated with increased risk for intermediate-term mortality (17.2% for TAVR and 12.7% for SAVR, RR 1.45, 95% CI 1.11-1.89, P = 0.006). In terms of periprocedural complications, TAVR was associated with reduced risk for bleeding and renal failure and an increase in vascular complications and Pacemaker implantation. In patients who are at low surgical risk, TAVR seems to be associated with increased mortality risk. Until more data in this population is available, SAVR should remain the treatment of choice for these patients.


Spending on Phased Clinical Development of Approved Drugs by the US National Institutes of Health Compared With Industry.
The launch of the Advanced Research Projects Agency for Health to advance new cures and address public concern regarding drug prices has raised questions about the roles of government and industry in drug development. To compare National Institutes of Health (NIH) spending on phased clinical development of approved drugs with that by industry. This cross-sectional study examined NIH funding for published research reporting the results of phased clinical trials of drugs approved between 2010 and 2019 and compared the findings with reported industry spending estimates. Data analysis was performed between May 2021 and August 2022 using PubMed data from January 1999 through October 2021 and NIH Research Portfolio Online Reporting Tools Expenditures and Results data from January 1999 through December 2020. Drugs approved between 2010 and 2019. National Institutes of Health funding for published research describing applied research on approved drugs, basic research on their biological targets, and phased clinical trials related to drugs approved between 2010 and 2019 were evaluated using Mann-Whitney U tests. All costs were inflation adjusted to 2018. National Institutes of Health funding for basic or applied research related to 386 of 387 drugs approved between 2010 and 2019 totaled $247.3 billion. Of this amount, $8.1 billion (3.3%) was related to phased clinical development. This funding contributed to 12 340 publications on phased clinical trial results involving 240 of 387 (62.0%) drugs. Average NIH spending was $33.8 million per drug, including $13.9 million per drug for phase 1, $22.2 million per drug for phase 2, and $12.9 million per drug for phase 3 trials. Spending by NIH on phased development represented 9.8% to 10.7% of estimated industry spending, including 24.6% to 25.3% of estimated phase 1, 21.4% to 23.2% of phase 2, and 3.7% to 4.3% of phase 3 costs. Considering 60 products for which estimated industry costs were publicly available, NIH spending on clinical trials was significantly lower than estimated industry spending (sum of averages, $54.9 million per drug; mean difference, $326.0 million; 95% CI, $235.6-$416.4 million; 2-tailed paired t test P < .001). More than 90% of NIH funding came through cooperative agreements or program projects and centers, while 3.3% of NIH funding came through investigator-initiated research projects. In this cross-sectional study, NIH funding for phased clinical development of drugs approved between 2010 and 2019 represented a small fraction of NIH spending on pharmaceutical innovation. This spending focused primarily on early-phase clinical trials and research capacity and was significantly less than estimated industry spending on clinical development. These results may inform the efficient allocation of government funding to advance pharmaceutical innovation.


Poly-3-hydroxybutyrate (PHB): a resorbable conduit for long-gap repair in peripheral nerves.
The repair of peripheral nerve injuries with an autologous nerve graft is still the treatment of choice, although it is widely recognised that the method is associated with donor-site morbidity and a suboptimal functional outcome. An alternative approach is to use a nerve conduit to provide a guidance channel for the regenerating nerve. This study investigates the potential of poly-3-hydroxybutyrate (PHB) nerve conduits to bridge long nerve gaps (up to 4 cm) in a rabbit common-peroneal-nerve injury model. Regeneration was assessed up to 63 days postoperatively, and compared with that achieved using nerve autografts. By 42 days, regenerating axons had bridged nerve gaps of all lengths in groups with nerve autografts and in those with PHB conduits. The regeneration distance increased with time but did not vary with gap length (P </= 0.009, 14 versus 21 days, PHB tube 2 cm, 3 cm and 4 cm, Mann-Whitney U -test). At 42 days, the area of immunostained regenerating fibres in the PHB group was greater than that in the nerve autograft group (P < 0.001, PHB versus autograft, 21 and 42 days, three-way analysis of variance (ANOVA)). These results suggest that PHB conduits support peripheral nerve regeneration up to 63 days, and that they are suitable for long-gap nerve injury repair.


Intercondyloid fractures of the humerus in the adult: surgical treatment and results.
The authors reviewed 14 cases of intercondyloid fracture of the humerus in the adult treated surgically between 1979 and 1989. After critically analysing the results, the surgical procedures, principal complications and their sequelae are discussed. They found a close relationship between the quality of the osteosynthesis and the quality of the results. However, despite the high percentage of favourable results, the authors emphasize the frequency of incomplete recovery of movement in the elbow joint.


Stride Pattern of the Lower Extremities Among Stride Types in Baseball Pitching.
The present study investigated the differences in the stride pattern of the lower extremities among different stride types in baseball pitchers with the aim of evaluating stride movement and skills to improve training effectiveness. Thirty elite male college baseball pitchers volunteered to pitch on an indoor-mound-like force plate, where motion data of their fastest strike trials were collected using an eight-camera motion analysis system at a 200-250 Hz sampling rate. Pelvis center trajectories of each participant were calculated and further categorized into three groups: tall-and-fall (TF), dip-and-drive (DD), and mixed (MX) pitchers. Motion analysis revealed that DD pitchers initiated pivot-knee extension and pivot-hip adduction earlier than TF pitchers and accelerated their bodies sooner than TF pitchers. In addition, TF pitchers accelerated their bodies forward by pivoting their legs until the middle of the arm-cocking and acceleration phases. The movement patterns of MX pitchers were similar to those of DD pitchers in terms of pivot leg, although this occurred a little later in the stride. Our findings are useful in developing training strategies for coaches, players, and trainers to better meet the demands of different pitching styles.


Factor VII and extrinsic pathway inhibitor in acute coronary disease.
This report describes studies on the activation of coagulation factor VII (FVII) and the inhibition of the extrinsic coagulation pathway in acute ischaemic heart disease. FVII and the inhibitor of the tissue thromboplastin-FVII complex, called extrinsic pathway inhibitor (EPI), were determined in plasma from 68 patients and compared to findings in 37 normal individuals. The mean FVII amidolytic activity, the mean FVII clotting activity, as well as the FVII clotting/FVII amidolytic ratio were not significantly different in the patient groups as compared to the controls. The fraction of FVII clotting activity that is sensitive to phospholipase C, 'the FVII-phospholipid complex', was 8% in controls, 19% (P less than 0.05) in patients with acute myocardial infarction, 15% (n.s.) in angina pectoris and 13% (n.s.) in heart failure/arrhythmia patients. The 'FVII-phospholipid complex' was highly significantly correlated to triglycerides in plasma in patients with acute myocardial infarction (r = 0.88, P less than 0.001) and angina pectoris (r = 0.89, P less than 0.001). The mean EPI levels were significantly increased in patients with acute myocardial infarction (132%), angina pectoris (134%), and heart failure (150%) as compared to the control population (110%). The FVII clotting/EPI ratio was significantly decreased both in patients with acute myocardial infarction and heart failure, whereas the FVII amidolytic/EPI ratio was significantly decreased only in the heart failure group. Apparently, in patients with acute ischaemic heart disease, a moderate increase in the procoagulant activity is accompanied by a marked increase in the anticoagulant activity of the extrinsic coagulation pathway, suggesting a balanced activation system.


Iheyamides A-C, Antitrypanosomal Linear Peptides Isolated from a Marine Dapis sp. Cyanobacterium.
Iheyamides A (1), B (2), and C (3), new linear peptides, were isolated from a marine Dapis sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Iheyamide A (1) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei (IC50 = 1.5 μM), but the other two analogues, iheyamides B (2) and C (3), did not (IC50 > 20 μM, respectively). The structure-activity relationship clarified that an isopropyl-O-Me-pyrrolinone moiety was necessary for the antitrypanosomal activity. Furthermore, the cytotoxicity of 1 against normal human cells, WI-38, was 10 times weaker than its antitrypanosomal activity (IC50 = 18 μM).


How long does the pharmacokinetic interaction between carbamazepine and quetiapine last after carbamazepine withdrawal?
Carbamazepine and quetiapine are drugs that are used as mood stabilizers in the treatment of bipolar disorders. A series of studies has shown that concurrent use of carbamazepine decreases quetiapine serum level due to induction of CYP3A enzymes by carbamazepine. In a 30-year-old bipolar patient with mania treated with quetiapine 1200 mg and carbamazepine 900 mg per day, we measured quetiapine serum level before and after carbamazepine withdrawal. No serum quetiapine was detected during concurrent use of carbamazepine and was lower than the therapeutic range almost 2 weeks after carbamazepine withdrawal. The patient suffered from sedation when her serum level of quetiapine was 181 ng/ml and because she was quiet we started slowly to decrease to a quetiapine dose of 600 mg. Her serum level (45 ng/ml) was again below therapeutic levels after 3 weeks of carbamazepine withdrawal. We hypothesize that induction of CYP3A lasts even after carbamazepine withdrawal. Our hypothesis was confirmed during the next treatment of mania. The patient had been off carbamazepine for 1 year and her serum level was four times higher (210 ng/ml) on 600 mg of quetiapine than 3 weeks after carbamazepine withdrawal. The influence of carbamazepine on CYP3A enzymes lasted at least 3 weeks after carbamazepine withdrawal which is in accordance with CYP3A de-induction lasting 3 weeks. This could be important information for psychiatrists to know that in some patients it is better to use a minimum washout period of 3 weeks for carbamazepine before new treatment with quetiapine.


How useful are prescribing indicators based on the DU90% method to distinguish the quality of prescribing between pharmacotherapy audit meetings with different levels of functioning?
The objective of the study was to assess the association between the quality of drug prescribing based on three indicator types derived from the DU90% method and different levels of functioning in pharmacotherapy audit meetings (PTAMs). The level of functioning in PTAMs in 2004 was assessed by a standard questionnaire. Data on prescriptions in 2004 by the GPs participating in the included PTAMs were extracted from the database of the Foundation for Pharmaceutical Statistics. Three types of DU90% indicators were computed for the seven mostly prescribed drug classes. With univariate and multivariate analyses of variance, differences in the results of three types of indicators for each of the seven drug classes were assessed according to the levels of PTAMs. For 84 PTAMs with varying levels of functioning, we found no association between the level of PTAM and the quality of prescribing for any of the indicators within the seven drug classes. In general, results gained of all PTAMs seemed to be high in quality for the aspects measured. It is difficult to define indicators based on the DU90% method, which can readily distinguish differences in the quality of drug prescribing between PTAMs with different levels of functioning. Indicators for prescribing should specifically meet relevant items in the quality of prescribing for certain drug classes. Items for classification of PTAM levels may need some reconsideration.


Introducing the open biomedical map of science.
This article introduces work in progress to develop a new, open biomedical map of science (OBMS) using the PubMed citation database. The new science map represents bimodal network relationships between journals and medical subject heading (MeSH) descriptors, based on a journal's articles indexed in the MEDLINE component of PubMed. We review the current efforts to use PubMed data in science of science studies and science mapping. As part of the development process, we compare the journals indexed in PubMed with journals included in the 2011 UCSD map of science to establish a baseline of disciplinary coverage of PubMed for the period 2009-2019. Journal article frequency is analyzed to establish the minimum number of citations required by a journal for inclusion in a map of science. A prototype OBMS is presented, and we discuss the strengths and weaknesses of the OBMS, as well as the next steps for using and productizing this new open map for general and free usage.


Clinical outcomes for 61 cases of hypopharyngeal cancer with synchronous esophageal cancer.
The aim of this research was to provide data from a single-center study of the treatment of synchronous hypopharyngeal cancer (HPC) and esophageal cancer (EC) with different treatment modalities. A total of 61 patients with synchronous HPC and EC were included in this study. Patients were treated with radiotherapy/chemoradiotherapy (28 cases), surgery (9 cases), palliative radiotherapy and/or chemotherapy (17 cases), or supportive care (7 cases). The median radiotherapy doses for EC and HPC in the radiotherapy/chemoradiotherapy group were 64.5 Gy (range, 0-70) and 70 Gy (range, 60-75.2), respectively. Seven patients in the surgery group received pharyngoesophagectomy with gastric pull-up reconstruction, and two received esophagectomy followed by radiotherapy at the hypopharynx. Cox proportional hazard analysis revealed that the outcome of active treatments, including surgery and radiotherapy/chemoradiotherapy, was better than that of conservative care. In survival analysis, patients in the surgery group tended to have a better 3-year overall survival rate than those in the radiotherapy/chemoradiotherapy group (55.6% vs 30.9%); however, this difference was not statistically different (P = 0.493). The two groups had similar 3-year progression-free survival rates (30.6% and 33.3%, P = 0.420). The current study suggested that radiotherapy/chemoradiotherapy should be considered as an important treatment modality in addition to surgery for synchronous HPC and EC.


Molecular appraisal of Indian animal isolates of Echinococcus granulosus.
Cystic echinococcosis (CE) has a wide host range and distinct entities, not only reflected phenotypically but also by genotypic variation. Considering this fact, this study was undertaken to characterize the Indian isolates of Echinococcus granulosus to find out difference between Indian cattle, buffalo and sheep isolates on the basis of random amplification of polymorphic DNA (RAPD) PCR and PCR mediated restriction fragment length polymorphism (PCRRFLP) of internal transcribed spacer gene 1 (ITS1). A total of 22 isolates of E. granulosus obtained from Indian cattle, buffalo and sheep (December 2004 - November 2005) were analysed by 26 random primers of 8-10 mers. After isolation of protoscoleces from fertile cyst, DNA was extracted, quantified and amplified by random primers. Internal transcribed spacer gene 1 (ITS1) was amplified using specific primer and digested by two restriction enzymes (Msp1 and Rsa1). Of the 26 primers, only two primers (5'ACC TGG ACA C3' and 5' TCA TCC GAG G3') could discriminate cattle, buffalo and sheep isolates collected from eastern part of India. Samples were further analysed by PCR mediated RFLP of internal transcribed spacer gene1 (ITS1) using two restriction enzymes (Msp1 and Rsa1). No ITS1 variants could be detected. Our findings showed genotypic variation among Indian animal isolates of E. granulosus on the basis of RAPD fingerprinting.


The burden of cardiac arrhythmias in sarcoidosis: a population-based inpatient analysis.
Cardiac involvement in the sarcoidosis is known to ensue with diverse clinical forms and its investigation is challenging at times. This article features the under-perceived burden, patterns, and outcomes of different arrhythmias, which may have a prognostic significance in patients with sarcoidosis. We queried the National Inpatient Sample (NIS) for 2010-2014 to recognize sarcoidosis, arrhythmia, and comorbidities affecting hospitalizations. The nationwide estimates were attained using discharge records. We assessed incidence and trends in sarcoidosis-related arrhythmia and consequential inpatient mortality, hospital length of stay (LOS), hospitalization charges and predictors of mortality with multivariate analysis. We identified 369,285 sarcoidosis-related hospitalizations. Of these, nearly one-fifth suffered from arrhythmias (n=73,424). The sarcoidosis patients developing arrhythmias were older (61.9 vs. 56.0 years) compared to those without. Males had the higher incidence of arrhythmias compared to females. Atrial fibrillation (Afib) (10.97%) was the most common subtype, followed by ventricular tachycardia (1.97%). There was a rising trend in arrhythmia-related hospital admissions and mortality among sarcoidosis, with Afib incidence displaying the highest increase. Traditional cardiac comorbidities were higher in the sarcoid-arrhythmia group. The arrhythmia group had significantly higher mortality (3.7% vs. 1.5%), mean hospital LOS (6.4 vs. 5.2 days) and hospital charges ($64,118 vs. $41,565) compared to non-arrhythmia group (P<0.001). Incident arrhythmia significantly increased the mortality odds in sarcoidosis (adjusted odds ratio, 2.06). The growing trend, deteriorating outcomes and higher mortality associated with sarcoid-related arrhythmias highlight the importance of timely diagnosis and aggressive management in this population.


Cell cycle arrest and cell survival induce reverse trends of cardiolipin remodeling.
Cell survival from the arrested state can be a cause of the cancer recurrence. Transition from the arrest state to the growth state is highly regulated by mitochondrial activity, which is related to the lipid compositions of the mitochondrial membrane. Cardiolipin is a critical phospholipid for the mitochondrial integrity and functions. We examined the changes of cardiolipin species by LC-MS in the transition between cell cycle arrest and cell reviving in HT1080 fibrosarcoma cells. We have identified 41 cardiolipin species by MS/MS and semi-quantitated them to analyze the detailed changes of cardiolipin species. The mass spectra of cardiolipin with the same carbon number form an envelope, and the C64, C66, C68, C70 C72 and C74 envelopes in HT1080 cells show a normal distribution in the full scan mass spectrum. The cardiolipin quantity in a cell decreases while entering the cell cycle arrest, but maintains at a similar level through cell survival. While cells awakening from the arrested state and preparing itself for replication, the groups with short acyl chains, such as C64, C66 and C68 show a decrease of cardiolipin percentage, but the groups with long acyl chains, such as C70 and C72 display an increase of cardiolipin percentage. Interestingly, the trends of the cardiolipin species changes during the arresting state are completely opposite to cell growing state. Our results indicate that the cardiolipin species shift from the short chain to long chain cardiolipin during the transition from cell cycle arrest to cell progression.


Thiazolidinediones versus metformin on improving abnormal liver enzymes in patients with type 2 diabetes mellitus: a meta-analysis.
Liver enzyme abnormalities are common in patients with type 2 diabetes. Currently, the inverse relationship between elevated liver enzymes and antidiabetics intake may be explained by rigorous treatment and good control. However, few studies have directly explored the influence of antidiabetics on abnormal liver function, especially the comparison between two insulin sensitizers-thiazolidinediones and metformin. Databases, including PubMed, Cochrane, CNKI, Wanfang and VIP were searched. Two reviewers performed independently. Meta-analysis was used when studies were homogeneous enough. Six studies, including 4726 patients with type 2 diabetes, were involved in this systematic review. Compared with metformin, thiazolidinediones significantly reduced the alanine transaminase, aspartate aminotransferase and gamma-glutamyl transpeptidase. Further subgroup analysis suggested that pioglitazone-treated participants showed vast improvement in decreasing alanine transaminase (MD = -13.70; 95% CI = -16.91 to -10.52; P < 0.00001; I2 = 1%), aspartate aminotransferase (MD = -3.51; 95% CI = -5.74 to -1.28; P = 0.002; I2 = 0%) and gamma-glutamyl transpeptidase (MD = -5.41; 95% CI = -9.40 to -1.42; P = 0.008; I2 = 0%), while rosiglitazone exhibited no difference in lowering corresponding liver enzyme levels. Besides, thiazolidinediones similarly decreased fasting plasma glucose. However, thiazolidinediones were inferior to metformin in lowering HbA1C and alkaline phosphatase. Additionally, no significant publication bias was seen. Thiazolidinediones may confer modest biological improvement of liver function in people with type 2 diabetes than metformin. But owing to the limited methodological quality, more clinical researches are warranted in the future.


Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation.
Percutaneous left atrial appendage closure (LAAC) is noninferior to vitamin K antagonists (VKAs) for preventing atrial fibrillation (AF)-related stroke. However, direct oral anticoagulants (DOACs) have an improved safety profile over VKAs, and their effect on cardiovascular and neurological outcomes relative to LAAC is unknown. This study sought to compare DOACs with LAAC in high-risk patients with AF. Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17) was a multicenter, randomized, noninferiority trial comparing LAAC with DOACs. Patients were eligible to be enrolled if they had nonvalvular AF; were indicated for oral anticoagulation (OAC); and had a history of bleeding requiring intervention or hospitalization, a history of a cardioembolic event while taking an OAC, and/or a CHA2DS2-VASc of ≥3 and HAS-BLED of >2. Patients were randomized to receive LAAC or DOAC. The primary composite outcome was stroke, transient ischemic attack, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure-/device-related complications. The primary analysis was by modified intention to treat. A high-risk patient cohort (CHA2DS2-VASc: 4.7 ± 1.5) was randomized to receive LAAC (n = 201) or DOAC (n = 201). LAAC was successful in 181 of 201 (90.0%) patients. In the DOAC group, apixaban was most frequently used (192 of 201; 95.5%). At a median 19.9 months of follow-up, the annual rates of the primary outcome were 10.99% with LAAC and 13.42% with DOAC (subdistribution hazard ratio [sHR]: 0.84; 95% confidence interval [CI]: 0.53 to 1.31; p = 0.44; p = 0.004 for noninferiority). There were no differences between groups for the components of the composite endpoint: all-stroke/TIA (sHR: 1.00; 95% CI: 0.40 to 2.51), clinically significant bleeding (sHR: 0.81; 95% CI: 0.44 to 1.52), and cardiovascular death (sHR: 0.75; 95% CI: 0.34 to 1.62). Major LAAC-related complications occurred in 9 (4.5%) patients. Among patients at high risk for stroke and increased risk of bleeding, LAAC was noninferior to DOAC in preventing major AF-related cardiovascular, neurological, and bleeding events. (Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation [PRAGUE-17]; NCT02426944).


New therapeutic targets in the management of urothelial carcinoma of the bladder.
Urothelial carcinoma of the bladder, despite the myriad of treatment approaches and our progressively increasing knowledge into its disease processes, remains one of the most clinically challenging problems in modern urological clinical practice. New therapies target biomolecular pathways and cellular mediators responsible for regulating cell growth and metabolism, both of which are frequently overexpressed in malignant urothelial cells, with the intent of inducing cell death by limiting cellular metabolism and growth, creating an immune response, or selectively delivering or activating a cytotoxic agent. These new and novel therapies may offer a potential for reduced toxicity and an encouraging hope for better treatment outcomes, particularly for a disease often refractory or not amenable to the current therapeutic approaches.


Expression and purification of protein segments encoded by the envelope and 3'-orf genes of human immunodeficiency virus type 1.
The pJL6 expression vector and its derivatives, pJLA16 and pANH-1, have been used for the synthesis and high-level expression in Escherichia coli of restriction enzyme fragments derived from the envelope and 3'-orf genes of the BH10 and BH8 clones, respectively, of the human immunodeficiency virus (HIV-1). These bacterially expressed proteins have been purified to apparent homogeneity by sequential detergent extraction, gel filtration, and reverse-phase high-performance liquid chromatography. The recombinant proteins have been used for the production of polyclonal and monoclonal antibodies, and the fusion proteins from the envelope gene are currently being evaluated for use as immunodiagnostic assay reagants.


Maternal dendrimer-based therapy for inflammation-induced preterm birth and perinatal brain injury.
Preterm birth is a major risk factor for adverse neurological outcomes in ex-preterm children, including motor, cognitive, and behavioral disabilities. N-acetyl-L-cysteine therapy has been used in clinical studies; however, it requires doses that cause significant side effects. In this study, we explore the effect of low dose N-acetyl-L-cysteine therapy, delivered using a targeted, systemic, maternal, dendrimer nanoparticle (DNAC), in a mouse model of intrauterine inflammation. Our results demonstrated that intraperitoneal maternal DNAC administration significantly reduced the preterm birth rate and altered placental immune profile with decreased CD8+ T-cell infiltration. Furthermore, we demonstrated that DNAC improved neurobehavioral outcomes and reduced fetal neuroinflammation and long-term microglial activation in offspring. Our study is the first to provide evidence for the role of CD8+ T-cell in the maternal-fetal interface during inflammation and further support the efficacy of DNAC in preventing preterm birth and prematurity-related outcomes.


Proteome analysis of irradiated endothelial cells reveals persistent alteration in protein degradation and the RhoGDI and NO signalling pathways.
Epidemiological studies indicate that radiation doses as low as 0.5 Gy increase the risk of cardiovascular disease decades after the exposure. The aim of the present study was to investigate whether this radiation dose causes late molecular alterations in endothelial cells that could support the population-based data. Human coronary artery endothelial cells were irradiated at 0.5 Gy (X-ray) and radiation-induced changes in the proteome were investigated after different time intervals (1, 7 and 14 d) using ICPL technology. Key changes identified by proteomics and bioinformatics were validated by immunoblotting and ELISA. The radiation-induced alteration of the endothelial proteome was characterized by sustained perturbation of Rho GDP-dissociation inhibitor (RhoGDI) and nitric oxide (NO) signalling pathways. At later time-points, this was accompanied by reduced proteasome activity, enhanced protein carbonylation indicating augmented oxidative stress, and senescence. These molecular changes are indicative of long-term premature endothelial dysfunction and provide a mechanistic framework to the epidemiological data showing increased risk of cardiovascular disease at 0.5 Gy.


The structure of hydrogenase-2 from Escherichia coli: implications for H2-driven proton pumping.
Under anaerobic conditions, Escherichia coli is able to metabolize molecular hydrogen via the action of several [NiFe]-hydrogenase enzymes. Hydrogenase-2, which is typically present in cells at low levels during anaerobic respiration, is a periplasmic-facing membrane-bound complex that functions as a proton pump to convert energy from hydrogen (H2) oxidation into a proton gradient; consequently, its structure is of great interest. Empirically, the complex consists of a tightly bound core catalytic module, comprising large (HybC) and small (HybO) subunits, which is attached to an Fe-S protein (HybA) and an integral membrane protein (HybB). To date, efforts to gain a more detailed picture have been thwarted by low native expression levels of Hydrogenase-2 and the labile interaction between HybOC and HybA/HybB subunits. In the present paper, we describe a new overexpression system that has facilitated the determination of high-resolution crystal structures of HybOC and, hence, a prediction of the quaternary structure of the HybOCAB complex.


Neighbourhood context and binge drinking from adolescence into early adulthood in a US national cohort.
Underage binge drinking is a serious health concern that is likely influenced by the neighbourhood environment. However, longitudinal evidence has been limited and few studies have examined time-varying neighbourhood factors and demographic subgroup variation. We investigated neighbourhood influences and binge drinking in a national cohort of US 10th grade students at four times (2010-2014; n = 2745). We estimated odds ratios (OR) for past 30-day binge drinking associated with neighbourhood disadvantage, personal and property crime (quartiles), and number of liquor, beer and wine stores within 5 km, and then evaluated whether neighbourhood associations differ by age, sex and race/ethnicity. Neighbourhood disadvantage was associated with binge drinking before 18 [OR = 1.54; 95% confidence interval (1.14, 2.08)], but not after 18 years of age. Property crime in neighbourhoods was associated with a higher odds of binge drinking [OR = 1.54 (0.96, 2.45)], an association that was stronger in early adulthood [4th vs 1st quartile: OR = 1.77 (1.04, 3.03)] and among Whites [4th vs 1st quartile: OR = 2.46 (1.03, 5.90)]. Higher density of liquor stores predicted binge drinking among Blacks [1-10 stores vs none: OR = 4.31 (1.50, 12.36)] whereas higher density of beer/wine stores predicted binge drinking among Whites [one vs none for beer: OR = 2.21 (1.06, 4.60); for wine: OR = 2.04 (1.04, 4.03)]. Neighbourhood conditions, particularly those related to economic circumstances, crime and alcohol outlet density, were related to binge drinking among young adults, but associations varied across age and individual characteristics.


Nanoparticle characterization: state of the art, challenges, and emerging technologies.
Nanoparticles have received enormous attention as a promising tool to enhance target-specific drug delivery and diagnosis. Various in vitro and in vivo techniques are used to characterize a new system and predict its clinical efficacy. These techniques enable efficient comparison across nanoparticles and facilitate a product optimization process. On the other hand, we recognize their limitations as a prediction tool, due to inadequate applications and overly simplified test conditions. We provide a critical review of in vitro and in vivo techniques currently used for evaluation of nanoparticles and introduce emerging techniques and models that may be used complementarily.


Gut microbiota metabolic potential correlates with body size between mulberry-feeding lepidopteran pest species.
Many insect pests rely on microbial symbionts to obtain nutrients or for defence, thereby allowing them to exploit novel food sources and degrade environmental xenobiotics, including pesticides. Although Lepidoptera is one of the most diverse insect taxa and includes important agricultural pests, lepidopteran microbiotas, particularly functional traits, have not been studied widely. Here, we provide a comprehensive characterization of the gut microbiota across multiple mulberry-feeding lepidopteran species, resolving both community structure and metabolic potential. Our results indicate abundant bacteria inside the gut of larval Lepidoptera. However, even though they were fed the same diet, the structures of the bacterial communities differed in four major mulberry pest species, suggesting host-specific effects on microbial associations. Community-level metabolic reconstructions further showed that although taxonomic composition varied greatly, carbohydrate and amino acid metabolism and membrane transporter were key functional capabilities of the gut bacteria in all samples, which may play basic roles in the larval gut. In addition, principal coordinate analysis (PCoA) of gut bacterial-predicted gene ontologies revealed specialized features of the microbiota associated with these mulberry pests, which were divided into two distinct clusters (macrolepidopterans and microlepidopterans). This pattern became even more prominent when further Lepidoptera species were involved. A suite of gut microbiota metabolic functions significantly correlated with larval size; the metabolism of terpenoids and polyketides, xenobiotics biodegradation and metabolism were specifically enriched in large species, while small larvae had enhanced nucleotide metabolism. Our report paves the way for uncovering the correlation between host phenotype and microbial symbiosis in this notorious insect pest group. © 2019 Society of Chemical Industry.


Complete supine percutaneous nephrolithotripsy comparison with the prone standard technique.
PCNL (percutaneous nephrolithotripsy) is usually performed in the prone position. The supine position has potential advantages comparing with the prone position. Our objective is comparison between the outcome of PCNL in the complete supine position and the standard prone position. A total of 80 patients who underwent PCNL from February 2008 to June 2008 evaluated in a prospective manner, were randomly divided into two groups: 40 patients underwent prone PCNL and 40 patients underwent complete supine PCNL. We performed complete supine PCNL with no rolled towel under the flank and no change in leg position. Results in both positions were compared regarding technical aspects, operative time, stone free rate, complications and hospital stay, and were analyzed using t-test and chi-square. We considered P < 0.05 as significant. Regardless the position, the pelvicaliceal system could be successfully approached in all patients. Mean operative time in supine group was 74.7 +/- 25.1 min and less than prone group (106.87 +/- 17.5) with a significant statistical difference (P < 0.0001). Stone free rate was 80% and 77.5% in prone and supine position respectively. Mean hospital stay was similar in both groups. Bleeding requiring transfusion in two groups had not significant statistical difference. We had not colon injury. PCNL in supine position is safe, effective and suitable for the patients. It offers the potential advantages of better urethral access, less patient handling, needing drape only once, ability to perform simultaneous PCNL and ureteroscopic procedures, better control of the airway during procedures, thus reducing over-all operative time compared to traditional prone position and performing PCNL while the surgeon is sitting. It may be considered for most patients requiring PCNL.


Correlates of late-life major depression: a comparison of urban and rural primary care patients.
The objective of this study was to determine whether factors associated with depression differ between elderly residents of rural and urban areas. The research design was cross-sectional and observational. The study subjects consisted of 926 Medicare primary care patients (650 urban and 276 rural) who were age 65+ and cognitively intact and had enrolled in a randomized, controlled Medicare demonstration. Major depression was identified by the Mini International Neuropsychiatric Interview. A logistic regression model was estimated that included a rural-urban indicator variable, additional independent variables, and interaction terms between the rural-urban indicator and independent variables that were significant at p <0.10. A total of 8.3% of the rural and 14.8% of the urban patients were identified as having major depression. Reporting 0-1 close friends (odds ratio [OR]: 6.86; 95% confidence interval [CI]: 2.18-21.58), 2+ emergency room visits during the past 6 months (OR: 4.00; 95% CI: 1.19-13.43), and more financial strain (OR: 1.50; 95% CI: 1.01-2.23) were associated with significantly higher likelihood of major depression among rural as compared with urban patients. The SF-36 Physical Component Summary score had a curvilinear relationship with major depression and was higher for urban patients. The predicted probability for major depression is lower for the rural patients when financial strain is low, about the same for rural and urban patients when strain is intermediate, and higher for rural patients when strain is high. Clinicians in rural areas should be vigilant for major depression among patients with very few close friends, several recent emergency department visits, and financial strain.


Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping.
Depending upon the UDP glucuronosyltransferase 1A1 (UGT1A1) genotype, patients are more or less susceptible to the risk of severe toxicity of irinotecan. As the US FDA-approved label of irinotecan (CPT-11, Camptosar) has been recently revised to include UGT1A1 genotype among potential risk factors for toxicity, it is expected that UGT1A1 genotyping will be increasingly used in patients undergoing irinotecan treatment. At present, the label states that *28/*28 (7/7) genotype patients are at higher risk of neutropenia and should be treated at a lower dose of irinotecan. Although effective alternative drugs (i.e., oxaliplatin) exist for metastatic colorectal cancer (the main indication of irinotecan), recent studies have confirmed that irinotecan has an important place in the management of this disease. We feel that now is the time for addressing questions around the UGT1A1*28 testing that many oncologists might have had but remained unanswered. For example, does the test have adequate sensitivity/specificity? Can the test results be effectively utilized to guide therapy of metastatic colorectal cancer patients? Is it possible that the *1/*1 (6/6) patients are underdosed? How can the genetic prediction of irinotecan toxicity be improved? Is the UGT1A1*28 test fully predictive of the UGT1A1 deficiency in patients who are not of Caucasian origin? Clinicians and investigators interested in a discussion of each of these points could find this article a useful source.


Feasibility of modified DLQI-based questionnaires for evaluation of clinical efficacy of herbal medicine in chronic skin diseases.
The efficacy of herbal medicines is thought to be ambiguous. The quality of life (QOL) of patients has been well-recognized as an useful measurement and we thought it to be a measurement of the efficacy of herbal medicine. The aim of this study was to examine the feasibility of modified DLQI-based questionnaires in evaluating the efficacy of herbal drugs in chronic skin diseases. 19 in-patients with chronic skin diseases were selected and treated by the herbal medicines just added on the previous drugs. By using the QOL-sheet, the patients' QOL before and after herbal treatments were converted to scores and we examined the scores to be a useful measurement. The QOL-sheet was made referring to the dermatology life quality index (DLQI) with our original questions and visual analogue scale (VAS) in Japanese. The herbal drugs were effective as the treatment with significant difference (P < 0.05) at clinical impression, DLQI and VAS. No significant differences of correlation between clinical impression, DLQI/DLQI with AQ and VAS/VAS with AQ was proved (P > 0.05). The QOL-sheet scored both by DLQI and by VAS may be useful to evaluate the efficacy of herbal medicines. However it may be necessary to reconsider the contents of our original questions.


Evidence-Based Practice and Chiropractic Care.
Evidence-based practice has had a growing impact on chiropractic education and the delivery of chiropractic care. For evidence-based practice to penetrate and transform a profession, the penetration must occur at 2 levels. One level is the degree to which individual practitioners possess the willingness and basic skills to search and assess the literature. Chiropractic education received a significant boost in this realm in 2005 when the National Center for Complementary and Alternative Medicine awarded 4 chiropractic institutions R25 education grants to strengthen their research/evidence-based practice curricula. The second level relates to whether the therapeutic interventions commonly employed by a particular health care discipline are supported by clinical research. A growing body of randomized controlled trials provides evidence of the effectiveness and safety of manual therapies.


Two new zinc(II) and mercury(II) complexes based on N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide): synthesis, crystal structures and antibacterial activities.
Reaction of N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide), C20H18F2N4O2, (LF), with zinc chloride and mercury(II) chloride produced different types and shapes of neutral coordination complexes, namely, dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ2N,O]zinc(II), [ZnCl2(C20H18F2N4O2)], (1), and dichlorido[N,N'-(cyclohexane-1,2-diylidene)bis(4-fluorobenzohydrazide)-κ4O,N,N',O']mercury(II), [HgCl2(C20H18F2N4O2)], (2). The organic ligand and its metal complexes are characterized using various techniques: IR, UV-Vis and nuclear magnetic resonance (NMR) spectroscopies, in addition to powder X-ray diffraction (PXRD), single-crystal X-ray crystallography and microelemental analysis. Depending upon the data from these analyses and measurements, a typical tetrahedral geometry was confirmed for zinc complex (1), in which the ZnII atom is located outside the bis(benzhydrazone) core. The HgII atom in (2) is found within the core and has a common octahedral structure. The in vitro antibacterial activities of the prepared compounds were evaluated against two different bacterial strains, i.e. gram positive Bacillus subtilis and gram negative Pseudomonas aeruginosa bacteria. The prepared compounds exhibited differentiated growth-inhibitory activities against these two bacterial strains based on the difference in their lipophilic nature and structural features.


The validation of plasma darunavir concentrations determined by the HPLC method for protease inhibitors.
Darunavir (DRV) is a new protease inhibitor used to treat human immunodeficiency virus (HIV) type-1. The aim of this study was to validate the determination of plasma DRV concentrations using the HPLC method, a simple procedure for simultaneous determination of seven HIV protease inhibitors and efavirenz. The calibration curve was linear (range of 0.13 to 10.36 microg/ml). The average accuracy ranged from 100.7 to 105.6%. Both the interday and intraday coefficients of variation were less than 6.7%, which was similar to or much lower than previously reported values by the LC/MS/MS method. It is concluded that HPLC can be used to determine plasma DRV concentrations and routinely in the clinical setting; thus, this HPLC method enables further study of DRV pharmacokinetics in conventional hospital laboratories.


Ureteroscopic management of upper-tract urothelial cancer: an exciting nephron-sparing option or an unacceptable risk?
To discuss the merits of the endoscopic management of upper-tract transitional-cell carcinoma (UTTCC). We present original data from our institution over an 8-year period and a review of some of the world literature. A discussion of the overall suitability of this modality for both clinician and patient is presented. A retrospective chart review was performed comprising operative logs, departmental databases, and pathologic registers. These sources were analyzed, and data were collected on all patients who underwent ureteroscopic treatment of UTTCC. Patients with at least 6 months of follow-up were included in the study. Forty-five patients (mean age 65 yrs) were identified who had undergone ureteroscopic treatment for UTTCC with either therapeutic or palliative intent between 1998 and 2006. Of these, 19 procedures were performed electively in patients with normal contralateral kidneys. Those patients with low-volume, low-grade tumors on biopsy and negative results of urinary cytologic evaluation recovered well, with few recurrences. None of this group progressed to radical surgery. Of 12 patients never considered for radical surgery, only 1 died of the disease after a median follow-up of 15 months. Elective ureteroscopic holmium:yttrium-aluminum-garnet laser ablation of UTTCC is a safe and effective treatment for a select group of patients. In our institution, patients with normal functioning contralateral kidneys are considered for endoscopic treatment and follow-up of their disease if disease is found to be of low grade and volume. Inadequacies in the staging of UTTCC mean that this may, in some cases, turn out to be suboptimal management, and therefore we maintain a low threshold for recommending radical surgery. For another group of patients with single kidneys, global renal dysfunction, or severe comorbidity, endoscopic treatment can prove a valuable palliative option even in those persons who have a large tumor bulk or relatively rapid disease recurrence.


The First Report of Macrolide-Resistant Bordetella pertussis Isolation in Japan.
We report the first detection of a macrolide-resistant Bordetella pertussis strain in Japan. The isolate was highly resistant to the macrolides (minimum inhibitory concentrations for erythromycin and clarithromycin: > 256 µg/ml, for azithromycin: 32 µg/ml) and A2047G mutation was identified in the 23S rRNA. The Multilocus Sequence Typing and Multilocus Variable Number of Tandem Repeat Analysis genotypes of this isolate were MT195 and ptxP1/ptxA1/prn1/fim3A/fhaB3, respectively, suggesting a relationship with the macrolide-resistant B. pertussis lineage currently found in China. This raises the possibility that macrolide-resistant B. pertussis has already fully spread in Japan. For a better control of B. pertussis infections, the surveillance for macrolide-resistant B. pertussis is essential in not only Japan, but also other Asian countries.


Abiotic and Biotic Factors Affecting Resting Spore Formation in the Mite Pathogen Neozygites floridana.
Neozygites floridana is an obligate mite pathogenic fungus in the Entomophthoromycota. It has been suggested that resting spores of this fungus are produced as a strategy to survive adverse conditions. In the present study, possible mechanisms involved in the regulation of resting spore formation were investigated in the hosts Tetranychus urticae and Tetranychus evansi. Abiotic and biotic factors mimicking conditions that we, based on earlier field studies, thought might induce resting spores in temperate and tropical regions were tested with isolates from Norway and Brazil. A total of 42 combinations of conditions were tested, but only one induced the formation of a high number of resting spores in only one isolate. The Brazilian isolate ESALQ1420 produced a large number of resting spores (51.5%) in T. urticae at a temperature of 11°C, photoperiod of 10L:14D, and light intensity of 42-46 ( μ mol m(-2) s(-1)) on nonsenescent plants (nondiapausing females). Resting spores of the Brazilian N. floridana isolate ESALQ1421 were found at very low levels (up to 1.0%). Small percentages of T. urticae with resting spores (0-5.0%) were found for the Norwegian isolate NCRI271/04 under the conditions tested. The percentages of resting spores found for the Norwegian isolate in our laboratory studies are similar to the prevalence reported in earlier field studies.


Platelet and leukocyte adhesion to albumin binding self-assembled monolayers.
This study reports the use of tetraethylene glycol-terminated self-assembled monolayers (EG(4) SAMs) as a background non-fouling surface to study the effect of an 18 carbon ligand (C18) on albumin selective and reversible adsorption and subsequent platelet and leukocyte adhesion. Surface characterization techniques revealed an efficient immobilization of different levels of C18 ligand on EG(4) SAMs and an increase of surface thickness and hydrophobicity with the increase of C18 ligands. Albumin adsorption increased as the percentage of C18 ligands on the surface increased, but only 2.5%C18 SAMs adsorbed albumin in a selective and reversible way. Adherent platelets also increased with the amount of immobilized C18. Pre-immersion of samples in albumin before contact with platelets demonstrated an 80% decrease in platelet adhesion. Pre-immersion in plasma was only relevant for 2.5%C18 SAMs since this was the only surface to have less platelet adhesion compared to buffer pre-immersion. EG(4) SAMs adhered negligible amounts of leukocytes, but surfaces with C18 ligands have some adherent leukocytes. Except for 10%C18 SAMs, which increased leukocyte adhesion after albumin pre-adhesion, protein pre-immersion did not influence leukocyte adhesion. It has been shown that a surface with a specific surface concentration of albumin-binding ligands (2.5%C18 SAMs) can recruit albumin selectively and reversibly and minimize the adhesion of platelets, despite still adhering some leukocytes.


Many roads lead to Rome: How improvisation and absorptive capacity affect entrepreneurial orientation and new venture performance relationship.
This paper develops and tests a model that highlights the roles of improvisation and absorptive capacity as important mediating mechanisms through which entrepreneurial orientation (EO) influences new venture performance. Furthermore, we examine the interactive effect of improvisation and absorptive capacity on new venture performance. The results show that (a) improvisation and absorptive capacity both mediate the relationship between EO and new venture performance; (b) the interaction between improvisation and absorptive capacity is positively related to new venture performance; (c) improvisation moderates the indirect relationship between EO and new venture performance via absorptive capacity; and (d) absorptive capacity moderates the mediation of improvisation in the relationship between EO and new venture performance. With these findings, this paper provides insights into how different learning modes can enhance the EO-performance relationship.


Echinococcus multilocularis Infection, Southern Ontario, Canada.
Alveolar echinococcosis, the disease caused by infection with the intermediate stage of the Echinococcus multilocularis tapeworm, is typically fatal in humans and dogs when left untreated. Since 2012, alveolar echinococcosis has been diagnosed in 5 dogs, 3 lemurs, and 1 chipmunk in southern Ontario, Canada, a region previously considered free of these tapeworms. Because of human and animal health concerns, we estimated prevalence of infection in wild canids across southern Ontario. During 2015-2017, we collected fecal samples from 460 wild canids (416 coyotes, 44 foxes) during postmortem examination and analyzed them by using a semiautomated magnetic capture probe DNA extraction and real-time PCR method for E. multilocularis DNA. Surprisingly, 23% (95% CI 20%-27%) of samples tested positive. By using a spatial scan test, we identified an infection cluster (relative risk 2.26; p = 0.002) in the western-central region of the province. The cluster encompasses areas of dense human population, suggesting zoonotic transmission.


Transgenic mouse models to study the role of APOE in hyperlipidemia and atherosclerosis.
Transgenic technologies have provided a series of very useful mouse models to study hyperlipidemia and atherosclerosis. Normally, mice carry cholesterol mainly in the high density lipoprotein (HDL) sized lipoproteins, and have low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol levels. These low LDL and VLDL levels are due to the very rapid metabolism of remnant clearance in mice, which hamper metabolic studies. In addition, due to the lack of atherogenic lipoproteins, mice will not readily develop atherosclerosis. This situation has changed completely, because to date, most known genes in lipoprotein metabolism have been used in transgenesis to obtain mice in which genes have been silenced or overexpressed. These experiments have yielded many mouse strains with high plasma lipid levels and a greater susceptibility for developing atherosclerosis. One of the most widely used strains are knock-out mice deficient for apoE, which is one of the central players in VLDL metabolism. Subsequently, a wide variety of other transgenic studies involving APOE have been performed elucidating the role of apoE and apoE mutants in lipolysis, remnant clearance, cellular cholesterol efflux and atherogenesis. In addition, the APOE mouse models are excellent tools for the development of gene therapy for hyperlipidemias.


[Does the administration of derivatives of vitamin D to dairy cows in late pregnancy for the prevention of parturient paresis affect the maternal-fetal mineral metabolism?].
Intramuscular injection of 1 alpha-hydroxyvitamin D3 (with or without 25-hydroxyvitamin D3) to highly pregnant dairy cows caused a significant increase of ionized calcium in blood and of total calcium and inorganic phosphate with a concomitant decrease of magnesium in blood plasma 3,5 +/- 1,9 days later (resp. 12-48 h a.p.). This brought about a higher Ca level at parturition preventing parturient paresis. The changes of maternal mineral and vitamin D status had no effect on the mineral concentrations of blood in newborn calves. However, the increase in calcium and phosphate concentrations in maternal blood after injection was accompanied by an increase of the minerals in the amniotic fluid reflecting their strong reciprocal exchange. On the other hand, the composition of allantoic fluid showed no significant changes. Therefore, analysis of both fetal fluids does not refer to disorders of fetal mineral metabolism. As a consequence, there seems to be no potential risk of intoxication after a prepartal injection of the substances to the mother for their offspring.


Hyperlipoproteinemia, hemostatic variables and thromboatherosclerosis.
A concept is gradually being established that certain forms of hyperlipoproteinemia are apt to be accompanied by disturbances of the hemostatic balance favouring fibrin deposition and the incorporation of microthrombi into the arterial wall. Author's clinical and laboratory observations emphasized that endogenous hypertriglyceridemia is often accompanied by raised plasma levels of fibrin stabilizing factor XIII, fibronectin and fibrinolytic inhibitors rendering the fibrin clots more resistant to fibrinolysis and more readily attached to the subendothelial layers of the vessel wall. Increased activity of vitamin K-dependent clotting factors partially counterbalanced by a rather high level of antithrombin III were also detected. Since endogenous hypertriglyceridemia is characterized by an accelerated synthesis and turnover of lipoproteins it may be suggested that this process somehow stimulates the hepatic production of the above-mentioned hemostatic variables. The subsequent alteration of the hemostatic balance is compatible with the localized character and the slow progression of thromboatherosclerosis.


[Serotonin and dumping syndrome (author's transl)].
5-hydroxyindole acetic acid, xanthurenic acid and kynurenin, --that is to say the major metabolites of serotonin, were measured in the urines of 31 patients with dumping syndrome. Serotonin concentrations were measured as well in peripheral venous blood before and after a glucose load in 47 patient with dumping syndrome. All values measured were in the normal range. Comparison of serotonin levels in peripheral and portal venous blood yielded normal results as well. It is therefore concluded, that serotonin does not play an essential role in the etiology of the dumping syndrome.


Reducing psychological distress and obesity through Yoga practice.
Yoga practice has been effectively prescribed in conjunction with other medical and yogic procedures in the management of severe psychosomatic diseases, including cancer, bronchial asthma, colitis, peptic and ulcer. It improves strength and flexibility, and may help control physiological variables such as blood pressure, lipids, respiration, heart rate, and metabolic rate to improve overall exercise capacity. The aim of this study is to evaluate the effects of Yogic Practice on anxiety/depression associated with obesity. Patients were recruited from the Department of Physiology, C.S.M. Medical University (erstwhile KGMU), Lucknow, Uttar Pradesh, India. A total of 272 subjects were divided into two groups: 1) group of 205 subjects (with yogic practice) and 2) a control group of 67 subjects (with aerobic exercise). Assessment of anxiety and depression were done by Hamilton Rating Scale. This study supports yoga as an effective tool with no diet restriction to improve anxiety and depression symptoms as well as obesity in obese subjects Incorporating yogic asana in the treatment protocol of patients suffering from anxiety and depression may prove beneficial in the long run.


Myofibroblastoma of male breast: a case report.
Myofibroblastoma of breast is an extremely rare, benign mesenchymal lesion composed ofmyofibroblasts. Less than seventy cases of this entity are reported in the literature. In spite of the widely varying morphological patterns, there are few characteristic cytological, histopathological, immunohistochemical, and ultrastructural features that permit its accurate identification among a vast group of mammary spindle cell tumours. We present the case ofa 60 year male presenting with a left breast nodule, interpreted as gynaecomastia on cytology. Histopathology however revealed characteristicfeatures of a myofibroblastoma, confirmed by immunohistochemistry.


Substrate-induced dissociation of glyceraldehyde-phosphate dehydrogenase detected by affinity chromatography. Study of subunit interactions by affinity sorption.
All four Nad-binding domains of the tetrameric apoglyceraldehyde-phosphate dehydrogenase (D-glyceraldehyde 3-phosphate:NAD+ oxidoreductase (phosphorylating), EC 220.127.116.11) displayed identical affinities (Kd = 4.8 x 10(-5) M) towards the chromophore of Blue Dextran. The enzyme species which contained only the most firmly bound NAD coupled the dye through the remaining free sites with the same affinity as the apoenzyme. The interaction of glyceraldehyde-phosphate dehydrogenase and Blue Dextran-Sepharose was characterized by the aid of an affiinity sorbent batch technique. We found that the apparent dissociation constant varied with enzyme concentration showing preferential binding in diulte solutions. This suggests that the monomeric and/or dimeric form(s) of glyceraldehyde-phosphate dehydrogenase have higher affinity towards the sorbent than the tetramer. The apparent Kd of the enzyme-Blue Dextran-Sepharose complex at low enzyme concentration was similar to the Ki of the competitive inhibition of enzyme activity by free Blue Dextran, i.e. about 10(-6) M. Glyceraldehyde 3-phosphate increased the binding of the enzyme to the immobilized dye in chromatographic experiments and decreased the apparent dissociation constant in the batch system if enzyme solutions of around 10(-6) M were examined. In more dilute solutions glyceraldehyde 3-phosphate had no effect on complex formation. These data suggest that glyceraldehyde 3-phosphate influences the interaction of the enzyme and the immobilized dye, first of all, by shifting the equilibrium of the different enzyme forms towards dissociation.


Pediatric performance with the Med-El Combi 40+ cochlear implant system.
Presented here are the results of speech perception measures and subjective scales from 68 children with 6 months of device experience and from 49 children with 12 months of experience in using the Med-El Combi 40+ cochlear implant system. All children demonstrated bilateral profound hearing loss before operation, and 90% experienced onset before 3 years of age, but their hearing losses had a broad range of causes. A battery of age-appropriate objective speech perception measures was administered, in addition to a battery of subjective auditory skill assessments. The group data indicate that the children showed a statistically significant improvement in a wide array of speech perception skills and auditory behaviors with this device. In addition, subjective therapist survey data indicated changes in primary receptive and expressive communication method with Combi 40+ device use. Individually, all children showed significant improvement on at least 1 of the speech perception measures used in the test battery. This evidence suggests that the Med-El Combi 40+ system can provide meaningful auditory information for profoundly deaf children, which in turn supports meaningful functional improvement in speech perception and communicative skill development.


Apo calmodulin binding to the L-type voltage-gated calcium channel Cav1.2 IQ peptide.
The influx of calcium through the L-type voltage-gated calcium channels (LTCCs) is the trigger for the process of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum, an essential step for cardiac contraction. There are two feedback mechanisms that regulate LTCC activity: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF), both of which are mediated by calmodulin (CaM) binding. The IQ domain (aa 1645-1668) housed within the cytoplasmic domain of the LTCC Cav1.2 subunit has been shown to bind both calcium-loaded (Ca2+CaM ) and calcium-free CaM (apoCaM). Here, we provide new data for the structural basis for the interaction of apoCaM with the IQ peptide using NMR, revealing that the apoCaM C-lobe residues are most significantly perturbed upon complex formation. In addition, we have employed transmission electron microscopy of purified LTCC complexes which shows that both apoCaM and Ca2+CaM can bind to the intact channel.


Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease.
In many countries, vaccines are used for the prevention of foot-and-mouth disease (FMD). However, because there is no protection against FMD immediately after vaccination, research and development on antiviral agents is being conducted to induce protection until immunological competence is produced. This study tested whether well-known chemicals used as RNA virus treatment agents had inhibitory effects on FMD viruses (FMDVs) and demonstrated that ribavirin showed antiviral effects against FMDV in vitro/in vivo. In addition, it was observed that combining the administration of the antiviral agents orally and complementary therapy with vaccines synergistically enhanced antiviral activity and preserved the survival rate and body weight in the experimental animals. Antiviral agents mixed with an adjuvant were inoculated intramuscularly along with the vaccines, thereby inhibiting virus replication after injection and verifying that it was possible to induce early protection against viral infection prior to immunity being achieved through the vaccine. Finally, pigs treated with antiviral agents and vaccines showed no clinical signs and had low virus excretion. Based on these results, it is expected that this combined approach could be a therapeutic and preventive treatment for early protection against FMD.


Bilateral Medial Medullary Infarct with Unique Radiological Presentation.
Bilateral medial medullary infarction is a rare subtype of stroke.The typical heart-shaped appearance on magnetic resonance imaging is pathognomonic for bilateral medial medullary syndrome. Vertebrobasilar dolichoectasia is a condition characterized by tortuous dilatation and marked enlargement of the basilar and vertebral arteries, and it may cause posterior circulation infarction. We present the case of a 55-year-old female patient with complaints of speech disorder, regression in consciousness, and difficulty breathing. Diffusion-weighted imaging examination was normal on arrival. In the cranial imaging after 24 hours, acute infarction was observed in the bilateral medial medullary area. Time-of-flight magnetic resonance angiography revealed vertebrobasilar dolichoectasia. In this report, a case of bilateral medial medullary infarction with a unique radiological appearance accompanied by vertebrobasilar dolichoectasia, which is rarely reported in the literature, is presented. Keywords: Stroke, infarct, bilateral medial medullary infarction, heart appearance.


A study of the spectrum of Acanthamoeba keratitis: a three-year study at a tertiary eye care referral center in South India.
To determine the epidemiological and clinical characteristics of Acanthamoeba keratitis and also to determine the sensitivity and specificity of smears in the detection of Acanthamoeba. A retrospective review of all culture-positive cases of Acanthamoeba keratitis seen between October 1999 and August 2002 was performed. Corneal scrapes were subjected to culture and microscopy using standard protocols. Out of 3183 consecutive patients with clinically diagnosed corneal ulcers evaluated, 33 (1.04%) were found to be due to Acanthamoeba. Twenty-four out of 33 (72.72%) were less than 51 years of age (P<0.001). All patients were from rural areas (P<0.001) and 26 (78.79%) of them were agricultural workers (P=0.031). All 33 had history of corneal injury (P<0.001) and 28 (84.85%) patients had injury with mud (P<0.001). All 33 (100%) patients had previous medical treatment (P=0.009) and 10 (30.3%) had used traditional eye medicines (P=0.183). A clinical pattern of ring infiltrate was characteristic in 15 (45.45%) patients. The diameter of the corneal ulcer was more than 6 mm in 27 (81.82%) eyes (P<0.001). Twenty-six (78.79%) patients had visual acuity of perception of light on initial presentation (P<0.001) and 24 (72.73%) had the same as their final visual outcome. The sensitivity of 10% potassium hydroxide (KOH) preparation was found to be higher (P<0.001) in the detection of Acanthamoeba cysts. The incidence of Acanthamoeba keratitis amongst the corneal ulcer patients was 1% in this setting and it was mainly due to corneal injury by mud. The KOH preparation is a sensitive diagnostic tool for the detection of Acanthamoeba. Delayed diagnosis or misdiagnosis and inappropriate antimicrobial therapy results in poor visual outcome.


[Guided bone regeneration beneath titanium foils].
The aim of this study was to examine the clinical and histological bony healing process beneath titanium foils used for guided tissue regeneration as well as of the Frios Algipore graft which was applied with autologous bone. 66 sinus floor elevations were carried out and examined over a period of three years and eight months. A success rate of 64% was recorded with foil incorporation. Complications occurred in form of primary and secondary disturbances in the healing process caused by exposure of the foil. 12 of the 66 foils had to be removed early. In all but one case, the augmented bone material was macroscopically well integrated despite the loss of the foil. Primary stability of the inserted dental implants into the ossified augmented site after operations of the sinus maxillaris was reached in all cases with absence of post-operative complications, and in 94% when there was postoperative exposure of the membrane. Histologically, a thin layer of connective tissue poor in cells but rich in collagen fibers appeared underneath the titanium foil. This was followed by newly-formed bony tissue transforming into osseous lamella parallel to the membrane underneath the new periost. In 65 out of 66 cases a sufficient amount of stable bone was built up locally suggesting good bio-compatibility and barrier function. Further, the foil also provided mechanical rest and supporting function for the space underneath. However, the occurrence of healing complications in 36% of the cases showed a need to improve on the titanium foils.


Taking common ground into account: Specifying the role of the mentalizing network in communicative language production.
Several studies have shown that communicative language production as compared to non-communicative language production recruits parts of the mentalizing or theory of mind network, yet the exact role of this network in communication remains underspecified. In this study, we therefore aimed to test under what conditions the mentalizing network contributes to communicative language production. We were especially interested in distinguishing between situations in which speakers have to consider which information they do or do not share with their addressee (common vs. privileged ground information). We therefore manipulated whether speakers had to distinguish between common and privileged ground in order to communicate efficiently with the listener, in addition to comparing language production in a communicative and a non-communicative context. Participants performed a referential communicative game in the MRI-scanner as well as a similar, non-communicative task. We found that the medial prefrontal cortex, a core region of the mentalizing network, is especially sensitive to communicative contexts in which speakers have to take their addressee's needs into account in order to communicate efficiently. In addition, we found neural differences between the communicative and the non-communicative settings before speakers started to plan their utterances, suggesting that they continuously update common ground in a communicative context.