Implementation fidelity of a self-management course for epilepsy: method and assessment.
Complex interventions such as self-management courses are difficult to evaluate due to the many interacting components. The way complex interventions are delivered can influence the effect they have for patients, and can impact the interpretation of outcomes of clinical trials. Implementation fidelity evaluates whether complex interventions are delivered according to protocol. Such assessments have been used for one-to-one psychological interventions; however, the science is still developing for group interventions. We developed and tested an instrument to measure implementation fidelity of a two-day self-management course for people with epilepsy, SMILE(UK). Using audio recordings, we looked at adherence and competence of course facilitators. Adherence was assessed by checklists. Competence was measured by scoring group interaction, an overall impression score and facilitator "didacticism". To measure "didacticism", we developed a novel way to calculate facilitator speech using computer software. Using this new instrument, implementation fidelity of SMILE(UK) was assessed on three modules of the course, for 28% of all courses delivered. Using the instrument for adherence, scores from two independent raters showed substantial agreement with weighted Kappa of 0.67 and high percent agreement of 81.2%. For didacticism, the results from both raters were highly correlated with an intraclass coefficient of 0.97 (p < 0.0001). We found that the courses were delivered with a good level of adherence (> 50% of scored items received the maximum of 2 points) and high competence. Groups were interactive (mean score: 1.9-2.0 out of 2) and the overall impression was on average assessed as "good". Didacticism varied from 42% to 93% of total module time and was not associated with the other competence scores. The instrument devised to measure implementation fidelity was reproducible and easy to use. The courses for the SMILE(UK) study were delivered with a good level of adherence to protocol while not compromising facilitator competence. ISRCTN57937389 .


Interaction patterns of methoprene-tolerant and germ cell-expressed Drosophila JH receptors suggest significant differences in their functioning.
Methoprene-tolerant (Met) and germ cell-expressed (Gce) proteins were shown to be juvenile hormone (JH) receptors of Drosophila melanogaster with partially redundant functions. We raised the question of where the functional differentiation of paralogs comes from. Therefore, we tested Met and Gce interaction patterns with selected partners. In this study, we showed the ability of Gce and its C-terminus (GceC) to interact with 14-3-3 in the absence of JH. In contrast, Met or Met C-terminus (MetC) interactions with 14-3-3 were not observed. We also performed a detailed structural analysis of Met/Gce interactions with the nuclear receptor fushi tarazu factor-1 (Ftz-F1) ligand-binding domain. We showed that GceC comprising an Ftz-F1-binding site and full-length protein interacts with Ftz-F1. In contrast to Gce, only MetC (not full-length Met) can interact with Ftz-F1 in the absence of JH. We propose that the described differences result from the distinct tertiary structure and accessibility of binding sites in the full-length Met/Gce. Moreover, we hypothesize that each interacting partner can force disordered MetC and GceC to change the structure in a partner-specific manner. The observed interactions seem to determine the subcellular localization of Met/Gce by forcing their translocation between the nucleus and the cytoplasm, which may affect the activity of the proteins. The presented differences between Met and Gce can be crucial for their functional differentiation during D. melanogaster development and indicate Gce as a more universal and more active paralog. It is consistent with the theory indicating gce as an ancestor gene.


Occurrence, Seasonal Distribution, and Molecular Characterization of Vibrio vulnificus, Vibrio cholerae, and Vibrio parahaemolyticus in Shellfish (Mytilus galloprovincialis and Ruditapes decussatus) Collected in Sardinia (Italy).
In this study, we investigated the occurrence, seasonal distribution, and molecular characterization of pathogenic vibrios in Mediterranean mussels (Mytilus galloprovincialis) and grooved carpet shells (Ruditapes decussatus) from two harvesting areas of Sardinia (Italy). Samples collected before and after depuration were submitted for qualitative and quantitative determination of Vibrio spp. Vibrio spp. isolates were presumptively identified by means of biochemical methods. Identification and virulence profile of Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio vulnificus were performed by molecular methods. The prevalence of Vibrio spp. in M. galloprovincialis and R. decussatus was, respectively, 96 and 77%. The averaged enumeration (mean ± standard deviation) of Vibrio spp. in samples of M. galloprovincialis and R. decussatus collected at the harvesting time was 2.04 ± 0.45 and 2.51 ± 0.65 log CFU/g, respectively. The average contamination levels in samples collected after purification were 2.28 ± 0.58 log CFU/g (M. galloprovincialis) and 2.12 ± 0.67 log CFU/g (R. decussatus). Four potentially pathogenic V. parahaemolyticus isolates (tdh+ or trh+) were recovered from grooved carpet shells samples. No isolate was tdh+/trh+. The presence of potentially pathogenic vibrios in Sardinian waters strengthens the need for rational purification practices under controlled conditions to guarantee the protection of consumers.


Coordinate activation of multidrug-resistance (P-glycoprotein) genes mdr2 and mdr3 during mouse liver regeneration.
We previously reported that only one of the three mouse multidrug-resistance (mdr) genes, mdr3, is activated in hepatocellular carcinomas (HCCs). The present study examined the expression of mdr family members during mouse liver regeneration after partial hepatectomy to determine whether the regeneration that occurs during hepatic tumorigenesis is responsible for mdr3 elevation in HCC. We demonstrated that in both C3H/HeN and B6C3/F1 mice strains, the levels of both mdr2 and mdr3 mRNAs coordinately increased five- to sevenfold 24 h after partial hepatectomy, whereas the levels of mdr1 mRNA were not statistically different from those in the controls. Forty-eight hours after partial hepatectomy, mdr mRNA levels decreased and in most cases returned to normal levels after 72 h. These results indicate that mdr3 induction during hepatocarcinogenesis is not due to liver regeneration alone.


Stacking faults in SiC nanowires.
SiC nanowires were obtained by a reaction between vapor silicon and multiwall carbon nanotubes, CNT, in vacuum at 1200 degrees C. Raman and IR spectrometry, X-ray diffraction and high resolution transmission electron microscopy, HRTEM, were used to characterize properties of SiC nanowires. Morphology and chemical composition of the nanowires was similar for all samples, but concentration of structural defects varied and depended on the origin of CNT. Stacking faults were characterized by HRTEM and Raman spectroscopy, and both techniques provided complementary results. Raman microscopy allowed studying structural defects inside individual nanowires. A thin layer of amorphous silicon carbide was detected on the surface of nanowires.


Dynamic Changes of the Microbial Community and Volatile Organic Compounds of the Northern Pike (Esox lucius) during Storage.
In this study, the quality (sensory evaluation, microbial enumerate, color, tvb-n (total volatile basic nitrogen), tca-soluble peptide (trichloroacetic acid-soluble peptide), muscle glucose, lactate, total sugar, Bas (Biogenic amines), VOCs (volatile organic compounds) and the microbial dynamic structure in samples stored at 4 °C were evaluated, and the relationship between VOCs and the diversity structure of microorganisms was also discussed. It was determined by sensory evaluation that the shelf life of samples was around 8 days. Protein and sugar were detected in large quantities by microorganisms in the later stage. At the same time, this also caused a large amount of Bas (biogenic amines) (tyramine, cadaverine, and putrescine). According to high-throughput amplicon sequencing, the initial microbiota of samples was mainly composed of Pseudomonas, Acinetobacter, Planifilum, Vagococcus, Hafnia, Mycobacterium, Thauera, and Yersinia. Among them, Pseudomonas was the most advantageous taxon of samples at the end of the shelf life. The minor fraction of the microbial consortium consisting of Vagococcus, Acinetobacter and Myroides was detected. The substances 3-methyl-1-butanol, ethyl acetate, and acetone were the main volatile components. The glucose, lactic acid, and total sugar were negatively correlated with Yersinia, Hafnia-Obesumbacterium, Thauera, Mycobacterium, and Planifilum; the proportion of these microorganisms was relatively high in the early stage. TVB-N and TCA-soluble peptides were positively correlated with Pseudomonas, Shewanella, Brochothrix, Vagococcus, Myroides, and Acinetobacter, and these microorganisms increased greatly in the later stage. The substance 3-methyl-1-butanol was positively correlated with Pseudomonas and negatively correlated with Mycobacterium. Ethyl acetate was associated with Hafnia-Obesumbacterium, Thauera, and Yersinia. Acetone was positively correlated with Acinetobacter.


Pain beliefs and readiness to change among adolescents with chronic musculoskeletal pain and their parents before an initial pain clinic evaluation.
To understand relationships between pain-related beliefs and readiness to change among treatment-seeking adolescents with chronic musculoskeletal pain and their parents. A total of 102 adolescent-parent dyads were recruited at the time of initial evaluation at a multidisciplinary pain management clinic. Dyads completed self-report measures to assess pain, catastrophizing, endorsement of a biopsychosocial perspective of pain, and readiness to change/motivation to adopt a self-management approach to pain coping. Agreement between adolescent-parent dyad reports of pain catastrophizing and readiness to change was found; however, adolescents were less likely to view pain as "affected by feelings and emotions" than parents. The hypothesis that greater pain catastrophizing would be correlated with less readiness to change was partially supported. Adolescent and parents who reported lower levels of endorsement of a biopsychosocial perspective were less willing to adopt a self-management approach to pain coping. Endorsement of a biopsychosocial perspective of pain aligned with readiness to change stages more consistently for parents. This study documents initial relationships among pain catastrophizing, biopsychosocial perspectives of pain, and readiness to engage in a self-management approach to pain coping for adolescents with chronic pain and their parents. Although agreement exists between dyads regarding catastrophizing and readiness to change, differences were noted in biopsychosocial perspective and dominant readiness to change stage before an initial pain clinic encounter. Findings are considered in terms of future research to advance knowledge regarding the role these factors may play in treatment adherence and outcomes.


Enzyme kinetics above denaturation temperature: a temperature-jump/stopped-flow apparatus.
We constructed a "temperature-jump/stopped-flow" apparatus that allows us to study fast enzyme reactions at extremely high temperatures. This apparatus is a redesigned stopped-flow which is capable of mixing the reactants on a submillisecond timescale concomitant with a temperature-jump even as large as 60 degrees C. We show that enzyme reactions that are faster than the denaturation process can be investigated above denaturation temperatures. In addition, the temperature-jump/stopped-flow enables us to investigate at physiological temperature the mechanisms of many human enzymes, which was impossible until now because of their heat instability. Furthermore, this technique is extremely useful in studying the progress of heat-induced protein unfolding. The temperature-jump/stopped-flow method combined with the application of structure-specific fluorescence signals provides novel opportunities to study the stability of certain regions of enzymes and identify the unfolding-initiating regions of proteins. The temperature-jump/stopped-flow technique may become a breakthrough in exploring new features of enzymes and the mechanism of unfolding processes.


cDNA cloning of the sodium-influx-stimulating peptide in the mollusc, Lymnaea stagnalis.
We isolated and characterized a cDNA clone, encoding the prohormone of the sodium-influx-stimulating (SIS) peptide of the freshwater snail Lymnaea stagnalis. The prohormone is cleaved to generate a signal peptide of 23 amino acids and a SIS peptide of 77 amino acids. The SIS peptide as encoded by the cDNA represents a novel and complex neuropeptide, which controls the activity of sodium pumps in the integument, pericardium, ureter and nephridial gland. In situ hybridization showed that the SIS-peptide gene is expressed by the neuroendocrine, so-called Yellow Cells of the central nervous system.


Postmastectomy irradiation in high-risk breast cancer patients. Present status of the Danish Breast Cancer Cooperative Group trials.
All pre- and postmenopausal high-risk breast cancer patients in the protocols DBCG 77 of the Danish Breast Cancer Cooperative Group received postmastectomy irradiation before randomization to either adjuvant systemic therapy or no such treatment. The actuarial loco-regional recurrence rate at 9 years was 6-17%, with the lowest rate in patients who also received additional adjuvant chemotherapy or tamoxifen. In a subsequent study (DBCG 82) the role of postmastectomy irradiation together with systemic treatment was evaluated in high-risk patients. Pre- and menopausal patients were randomized to postmastectomy irradiation + CMF (cyclophosphamide, methotrexate, 5-fluorouracil), CMF alone or CMF + TAM (tamoxifen). Postmenopausal patients were randomized to postmastectomy irradiation + TAM, TAM or CMF + TAM. At 4 years the loco-regional recurrence rate was significantly lower in the irradiated patients (5-7% vs. 23-33%). Further, disease-free survival was significantly improved in both pre- and postmenopausal irradiated patients compared with those who had only systemic treatment. At present, there are no significant differences between survival in the treatment groups. Thus, adjuvant systemic treatment alone (chemotherapy and/or tamoxifen) did not prevent loco-regional recurrences in high-risk patients after mastectomy and axillary lymph node sampling. However, a longer observation time is necessary to evaluate the consequence of primary optimal loco-regional tumour control in high-risk breast cancer patients with respect to survival.


Spatial structuring of a Legionella pneumophila population within the water system of a large occupational building.
The diversity of Legionella pneumophila populations within single water systems is not well understood, particularly in those unassociated with cases of Legionnaires' disease. Here, we performed genomic analysis of 235 L. pneumophila isolates obtained from 28 water samples in 13 locations within a large occupational building. Despite regular treatment, the water system of this building is thought to have been colonized by L. pneumophila for at least 30 years without evidence of association with Legionnaires' disease cases. All isolates belonged to one of three sequence types (STs), ST27 (n=81), ST68 (n=122) and ST87 (n=32), all three of which have been recovered from Legionnaires' disease patients previously. Pairwise single nucleotide polymorphism differences amongst isolates of the same ST were low, ranging from 0 to 19 in ST27, from 0 to 30 in ST68 and from 0 to 7 in ST87, and no homologous recombination was observed in any lineage. However, there was evidence of horizontal transfer of a plasmid, which was found in all ST87 isolates and only one ST68 isolate. A single ST was found in 10/13 sampled locations, and isolates of each ST were also more similar to those from the same location compared with those from different locations, demonstrating spatial structuring of the population within the water system. These findings provide the first insights into the diversity and genomic evolution of a L. pneumophila population within a complex water system not associated with disease.


Stereoselective 1,2-cis glycosylation of 2-O-allyl protected thioglycosides.
The technique of intramolecular aglycon delivery (IAD), whereby a glycosyl acceptor is temporarily appended to a hydroxyl group of a glycosyl donor is an attractive method that can allow the synthesis of 1,2-cis glycosides in an entirely stereoselective fashion. 2-O-Allyl protected thioglycoside donors are excellent substrates for IAD, and may be glycosylated stereoselectively through a three-step reaction sequence. This sequence consists of quantitative yielding allyl bond isomerisation, to produce vinyl ethers that can then undergo N-iodosuccinimide mediated tethering of the desired glycosyl acceptor, and subsequent intramolecular glycosylation, to yield either alpha-glucosides or beta-mannosides accordingly. Although attempted one-pot tethering and glycosylation is hampered by competitive intermolecular reaction with excess glycosyl acceptor, this problem can be simply overcome by the use of excess glycosyl donor. Allyl mediated IAD is a widely applicable practical alternative to other IAD approaches for the synthesis of beta-mannosides, that is equally applicable for alpha-gluco linkages. It is advantageous in terms of both simplicity of application and yield, and in addition has no requirement for cyclic 4,6-protection of the glycosyl donor.


Spin-Polarizing Interferometric Beam Splitter for Free Electrons.
A spin-polarizing electron beam splitter is described that relies on an arrangement of linearly polarized laser waves of nonrelativistic intensity. An incident electron beam is first coherently scattered off a bichromatic laser field, splitting the beam into two portions, with electron spin and momentum being entangled. Afterwards, the partial beams are coherently superposed in an interferometric setup formed by standing laser waves. As a result, the outgoing electron beam is separated into its spin components along the laser magnetic field, which is shown by both analytical and numerical solutions of Pauli's equation. The proposed laser field configuration thus exerts the same effect on free electrons as an ordinary Stern-Gerlach magnet does on atoms.


Differential requirements for RAD51 in Physcomitrella patens and Arabidopsis thaliana development and DNA damage repair.
RAD51, the eukaryotic homolog of the bacterial RecA recombinase, plays a central role in homologous recombination (HR) in yeast and animals. Loss of RAD51 function causes lethality in vertebrates but not in other animals or in the flowering plant Arabidopsis thaliana, suggesting that RAD51 is vital for highly developed organisms but not for others. Here, we found that loss of RAD51 function in the moss Physcomitrella patens, a plant of less complexity, caused a significant vegetative phenotype, indicating an important function for RAD51 in this organism. Moreover, loss of RAD51 caused marked hypersensitivity to the double-strand break-inducing agent bleomycin in P. patens but not in Arabidopsis. Therefore, HR is used for somatic DNA damage repair in P. patens but not in Arabidopsis. These data imply fundamental differences in the use of recombination pathways between plants. Moreover, these data demonstrate that the importance of RAD51 for viability is independent of taxonomic position or complexity of an organism. The involvement of HR in DNA damage repair in the slowly evolving species P. patens but not in fast-evolving Arabidopsis suggests that the choice of the recombination pathway is related to the speed of evolution in plants.


Autologous bone marrow mononuclear cell implantation induces angiogenesis and bone regeneration in a patient with compartment syndrome.
A 28-year-old man developed compartment syndrome in the right lower leg after fracture of the tibia and fibula. Despite fasciotomy, many arteries collapsed and union of the tibial and fibula fractures did not occur. Autologous bone marrow mononuclear cell (BMMNC) implantation for therapeutic angiogenesis and subsequent bone regeneration was performed and 4 weeks later, angiography showed a marked increase in collateral vessels surrounding the tibial fracture, and union was completed 6 months later. BMMNC implantation therapy might provide therapeutic angiogenesis and osteogensis in patients with compartment syndrome.


Surgical management of pulmonary metastases from colorectal cancer in 153 patients.
Surgery has become a recognized therapeutic means in selected patients with pulmonary metastases from colorectal origin. We reviewed our experience in the surgical treatment of 153 patients with pulmonary colorectal metastases and investigated factors affecting survival. A retrospective analysis of the records of all patients (n = 153) with pulmonary metastases from colorectal cancer who underwent thoracotomy between 1978 and 2003 at a single surgical center was performed. One hundred fifty-three patients with pulmonary metastases from colon (n = 61) or rectal (n = 92) cancer underwent 180 thoracotomies. The 2- and 5-year probabilities of survival after the first thoracotomy were 64% and 37%, respectively. Sex, age, site, International Union Against Cancer stage of the primary tumor, prethoracotomy carcinoembryonic antigen level, size of metastases, and previous resection of hepatic metastases were not found to be statistically significant prognostic factors. Number of metastases (solitary vs. multiple), mode of operation (wedge vs. anatomical resection), disease-free interval (DFI; > 36 months), negative hilar or mediastinal lymph node status, resection margin > 10 mm, and administration of intraoperative blood substitution were predictors of a longer survival duration by univariate analysis, but only number of metastases (P = .019), mode of operation (P = .004), DFI (P = .027), and intraoperative blood substitution (P = .002) were identified as independent prognostic factors by multivariate analysis. Pulmonary resection for metastases from colorectal cancer is safe and results in long-term survival in selected patients. Single metastases, anatomical resection, intraoperative blood substitution, and DFI > 36 months seem to be the most reliable predictors of survival.


Prevalence of non-alcoholic fatty liver disease in patients with nephrotic syndrome: A population-based study.
Non-alcoholic fatty liver disease (NAFLD) is a global health concern with a prevalence of about 25% amongst United States adults. Its increased prevalence is attributed to increase in patients with obesity and metabolic syndrome, partly due to similar mechanisms of injury. Nephrotic syndrome (NS) is a clinical entity resulting from extensive proteinuria leading to hypoalbuminemia, hyperlipidemia, edema, and other complications. Given its association with hyperlipidemia, there is concern that patients with NS may be at increased risk of NAFLD. To perform a cross-sectional population-based study to investigate the prevalence and risk factors of NAFLD in patients with NS. A large multicenter database (Explorys Inc., Cleveland, OH, United States) was utilized for this retrospective cohort study. A cohort of 49700 patients with a diagnosis of "Non-Alcoholic fatty liver disease" using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) between 1999-2022 was identified. Inclusion criteria were age ≥ 18 years, presence of NAFLD, presence of NS. There were no specific exclusion criteria. Univariate and multivariate analysis were performed to adjust for multiple risk factors including age, gender, Caucasian race, NS, type II diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease. Statistical analysis was conducted using R, and for all analyses, a 2-sided P value of < 0.05 was considered statistically significant. Among the 78734750 individuals screened in this database, there were a total of 49700 subjects with NAFLD. In univariate analysis, the odds of having NAFLD in patients with NS, type 2 diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease were 14.84 [95% confidence interval (95%CI) 13.67-16.10], 17.05 (95%CI 16.78-17.32), 6.99 (95%CI 6.87-7.11), 13.61 (95%CI 13.38-13.84), 19.19 (95%CI 18.89-19.50), 29.09 (95%CI 28.26--29.95), and 9.05 (95%CI 8.88-9.22), respectively. In multivariate analysis, the odds of having NAFLD amongst patients with NS were increased to 1.85 (95%Cl 1.70-2.02), while the odds were also remained high in patients that have type 2 diabetes mellitus [odds ratio (OR) 3.84], hypothyroidism (OR 1.57), obesity (OR 5.10), hyperlipidemia (OR 3.09), metabolic syndrome (OR 3.42) and chronic kidney disease (OR 1.33). Patients with NS are frequently found to have NAFLD, even when adjusting for common risk factors. Hence, clinicians should maintain a high index of suspicion regarding presence of NAFLD in patients with NS.


Ionizing radiation--understanding and acceptance.
A written survey about perceived radiation risks was conducted among three groups of a total of 400 individuals. Seventy-seven (26%) of the respondents were radiation workers, 35 (12%) were medical doctors without professional exposure, and 177 (68%) belonged to the general population. Even if the sample is not representative of the Romanian population as a whole, some interesting conclusions can be made. The level of anxiety toward radiation, expressed as a hazard perception index, is significantly lower in radiation workers when compared to medical doctors and the general population (0.81 +/- 0.94, 1.42 +/- 1.21, and 1.72 +/- 1.34, respectively, p < 0.001). Hazard perception index values also varied with the education status, with lowest values among medical university graduates and highest among public school graduates (p < 0.001). Both university-graduated groups significantly differ from the non-university groups (p < 0.05). Knowledge about radiation and emergency plans for nuclear accidents/incidents was also correlated with hazard perception, with the results confirming the hypothesis that better knowledge is associated with lower radiation hazard perception. The extent to which people accept civilian nuclear power is also related to hazard perception and knowledge. The way people perceive the radiation risk differed among the three groups. Different levels of risk perception were associated with radiation from nuclear energy and diagnostic x rays. It is important that radiological protection authorities develop new plans and materials for communicating with the general public in order to improve knowledge of ionizing radiation, radiation risks, and the safety of civilian nuclear energy employment.


Phase III, Randomized, Double-Blind Study Comparing the Efficacy, Safety, and Immunogenicity of SB3 (Trastuzumab Biosimilar) and Reference Trastuzumab in Patients Treated With Neoadjuvant Therapy for Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer.
Purpose This phase III study compared SB3, a trastuzumab (TRZ) biosimilar, with reference TRZ in patients with human epidermal growth factor receptor 2-positive early breast cancer in the neoadjuvant setting ( ClinicalTrials.gov identifier: NCT02149524). Patients and Methods Patients were randomly assigned to receive neoadjuvant SB3 or TRZ for eight cycles concurrently with chemotherapy (four cycles of docetaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant SB3 or TRZ. The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set; equivalence was declared if the 95% CI of the ratio was within 0.785 to 1.546 or the 95% CI of the difference was within ± 13%. Secondary end points included comparisons of total pathologic complete response rate, overall response rate, event-free survival, overall survival, safety, pharmacokinetics, and immunogenicity. Results Eight hundred patients were included in the per-protocol set (SB3, n = 402; TRZ, n = 398). The bpCR rates were 51.7% and 42.0% with SB3 and TRZ, respectively. The adjusted ratio of bpCR was 1.259 (95% CI, 1.085 to 1.460), which was within the predefined equivalence margins. The adjusted difference was 10.70% (95% CI, 4.13% to 17.26%), with the lower limit contained within and the upper limit outside the equivalence margin. The total pathologic complete response rates were 45.8% and 35.8% and the overall response rates were 96.3% and 91.2% with SB3 and TRZ, respectively. Overall, 96.6% and 95.2% of patients experienced one or more adverse event, 10.5% and 10.7% had a serious adverse event, and 0.7% and 0.0% had antidrug antibodies (up to cycle 9) with SB3 and TRZ, respectively. Conclusion Equivalence for efficacy was demonstrated between SB3 and TRZ on the basis of the ratio of bpCR rates. Safety and immunogenicity were comparable.


Inhibitory effects of imatinib on vitamin D₃ synthesis in human keratinocytes.
Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of the BCR‑ABL1 fusion gene, a constitutively active, oncogenic tyrosine kinase that is responsible for the clinical features of CML. Tyrosine kinase inhibitors, such as imatinib, have markedly altered the treatment of CML. However, tyrosine kinase inhibitors are associated with side effects on bone metabolism, in adult and pediatric patients. Vitamin D3 is involved in the complex cycle of bone remodeling, therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line, using commercially available enzyme assays. Imatinib was shown to significantly reduce the production of calcidiol and calcitriol. Based on interaction studies of imatinib with the cytochrome P450 (CYP450) inhibitors VID400 and ketoconazole, it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by CYP27B1, which is involved in vitamin D3 metabolism.


Late Type 3b Endoleak Mimicking Type 2 Endoleak after Endovascular Aortic Aneurysm Repair.
Endovascular abdominal aortic aneurysm (AAA) repair has been widely used for the treatment of AAA as a safe and efficient method, but endoleaks causing persistent expansion of aneurysm sac may cause aneurysmal rupture and death. Type 3 endoleak is rare but a predominant cause of late rupture. Type 3b endoleak can be misdiagnosed as type 2 endoleak, which is more frequent. Here we report two cases of type 3b endoleak mimicking type 2 endoleak, which were successfully treated by open surgery of partial explantation of the stent-graft and endoaneurysmal interposition graft replacement.


The Oldest Recorded Case of Acromegaly and Gigantism in Iran.
Here we commemorate the character and academic authority of Prof. Zabiholah Gorban (1903-2006), the founder of Shiraz medical school. No doubt, in the scope of history of contemporary medicine, he has been efficient and effective. With respect to this fact, his article on a rare case described in Acta anatomica published in Iran in 1966, entitled (Observations on a giant skeleton) is browsed and reviewed. A case named Siah Khan with combined acromegaly and gigantism that appears to have letters to say still after nearly half a century.


Phase I study of MEN-10755, a new anthracycline in patients with solid tumours: a report from the European Organization for Research and Treatment of Cancer, Early Clinical Studies Group.
A phase I study was performed with MEN-10755, a novel anthracycline with promising preclinical antitumour activity, in patients with solid tumours to determine the maximum tolerated dose (MTD); the dose-limiting toxicities (DLTs); to document antitumour activity; and to propose a safe dose for phase II evaluation. MEN-10755 at a starting dose of 15 mg/m2/week was given by short intravenous infusion weekly for 3 weeks and cycles were repeated every 28 days. Twenty-four patients received 55 cycles. Doses of MEN-10755 were 15, 30, 40 and 45 mg/m2. At a dose of MEN-10755 45 mg/m2, treatment could not be given as planned due to neutropenia and one patient developed a decrease in cardiac function. This dose level was considered to be the MTD. Chemotherapy-naive patients could be treated with 40 mg/m2/week, and only one DLT (grade 4 neutropenia) was observed. At that dose, three of six chemotherapy pretreated patients developed a DLT during their first treatment cycle: one patient developed a grade 4 thrombocytopenia, one patient a grade 4 neutropenia and one patient developed a grade 3 acute hypersensitivity reaction resulting in discontinuation of treatment. At this dose level, one other patient did not receive treatment on day 15 as planned due to grade 3 neutropenia. No responses were observed. MEN-107555 at a dose of 30 mg/m2/week in pretreated patients and 40 mg/m2/week in chemotherapy-naive patients for three consecutive weeks followed by 1 week rest is recommended for phase II testing.


GRP94-associated enzymatic activities. Resolution by chromatographic fractionation.
GRP94 (gp96), which performs established functions as a molecular chaperone and immune system modulator, has been reported to display a number of intrinsic enzymatic activities, including ATP hydrolysis, protein phosphorylation, and aminopeptidase. In observing that GRP94 co-purified with bacterial beta-galactosidase through multiple chromatographic steps, we have examined the hypothesis that the reported enzymatic activities of GRP94 may reflect co-purification of contaminant enzymes, rather than intrinsic catalytic functions. In subjecting GRP94 to increasingly stringent chromatographic purification, we report that a GRP94 carboxyl-terminal directed protein kinase activity could be separated from GRP94 by heparin affinity chromatography. Analysis of the kinase substrate specificity indicates that this kinase is distinct from casein kinase II, which is known to co-purify with GRP94. Electrophoretically pure GRP94 displayed low, but significant levels of aminopeptidase activity. Further purification of GRP94 by anion exchange and heparin affinity chromatography yielded resolution of GRP94 from the aminopeptidase activity. Furthermore, exhaustive trypsinolysis of GRP94 preparations displaying aminopeptidase activity yielded complete proteolysis of GRP94 but did not affect aminopeptidase activity. These results are discussed with respect to current models for GRP94 function and the role of such co-purifying (poly)peptides in the generation of GRP94-dependent cellular immune responses.


Comparative study of activation analyses for the determination of trace halogens in geological and cosmochemical samples.
Halogens (fluorine, chlorine, bromine and iodine) were determined by activation analyses (neutron activation analysis (NAA), photon activation analysis (PAA) and prompt gamma-ray analysis (PGA)) for geological and cosmochemical solid samples. We studied how each analytical method was for the determination of trace amounts of halogens in rock samples. Radiochemical NAA (RNAA) showed the highest analytical reliability for three halogens (chlorine, bromine and iodine), whereas a set of four halogens (fluorine, chlorine, bromine and iodine) could be determined in principle by radiochemical PAA (RPAA) from a single specimen. Although it is a non-destructive method, PGA showed an analytical sensitivity for chlorine comparable to those of RNAA and RPAA.


UK audit of quantification of left-ventricular function using gated myocardial perfusion imaging.
The aim of the study was to evaluate UK-wide interinstitutional reproducibility of left-ventricular functional parameters, end-systolic volume, end-diastolic volume and ejection fraction, obtained from gated myocardial perfusion imaging (GMPI) studies using technetium-99m-labelled radiopharmaceuticals. The study was carried out by the UK Institute of Physics and Engineering in Medicine Nuclear Medicine Software Quality Group. Ten anonymized clinical GMPI studies, five with normal perfusion and five with perfusion defects, were made available in DICOM and proprietary formats for download and through manufacturers' representatives. Two of the studies were duplicated in order to assess intraoperator repeatability, giving a total of 12 studies. Studies were made available in 8 and 16 frames/cycle. A total of 58 institutions across England, Scotland, Wales and Northern Ireland participated in this study using six different computer packages. Studies were processed at centres using their normal clinical computers and software. The overall mean±SD ejection fraction for all centres was 58.5±3%; the mean end-diastolic volume was 114±12 ml and the mean end-systolic volume was 54±6 ml. The results were affected by the number of frames per cycle and by the postprocessing computer package, but not by the reconstruction filter in the filtered back-projection. Calculation of functional parameters from GMPI using technetium-99m-labelled radiopharmaceuticals is reliable and shows limited variability across the UK.


De novo assembly and analysis of the transcriptome of the Siberian wood frog Rana amurensis.
The Siberian wood frog Rana amurensis Boulenger, 1886 is the most hypoxia-tolerant amphibian. It can survive for several months in an almost complete absence of oxygen. Little is known about the mechanisms of this remarkable resilience, in part because studies of amphibian genomes are impeded by their large size. To make the Siberian wood frog more amenable for genetic analysis, we performed transcriptome sequencing and de novo assembly for the R. amurensis brain under hypoxia and normoxia, as well as for the normoxic heart. In order to build a de novo transcriptome assembly of R. amurensis, we utilized 125-bp paired-end reads obtained from the brain under normoxia and hypoxia conditions, and from the heart under normoxia. In the transcriptome assembled from about 100,000,000 reads, 81.5 % of transcripts were annotated as complete, 5.3 % as fragmented, and 13.2 % as missing. We detected 59,078 known transcripts that clustered into 22,251 genes; 11,482 of them were assigned to specific GO categories. Among them, we found 6696 genes involved in protein binding, 3531 genes involved in catalytic activity, and 576 genes associated with transporter activity. A search for genes encoding receptors of the most important neurotransmitters, which may participate in the response to hypoxia, resulted in a set of expressed receptors of dopamine, serotonin, GABA, glutamate, acetylcholine, and norepinephrine. Unexpectedly, no transcripts for histamine receptors were found. The data obtained in this study create a valuable resource for studying the mechanisms of hypoxia tolerance in the Siberian wood frog, as well as for amphibian studies in general.


Replication of cranial gunshot wounds.
It is possible to differentiate between entrance and exit wounds in bone by examining the specimen concerned. Because of the evidential usefulness of providing jurists or members of a jury with such specimens, we describe an easy and reliable method for replicating gunshot wounds in the human skull utilizing dental materials and methods.


Accumulation of norfloxacin by Mycobacterium aurum and Mycobacterium smegmatis.
The modified fluorescence method was used to determine the accumulation of norfloxacin by Mycobacterium aurum A+ and Mycobacterium smegmatis mc(2)155. By using an exogenous norfloxacin concentration of 10 microg/ml, a steady-state concentration (SSC) of 160 to 180 ng of norfloxacin/mg of cells was obtained for M. aurum, and an SSC of 120 to 140 ng of norfloxacin/mg of cells obtained for M. smegmatis. For both species of mycobacteria, the SSC was achieved within 5 min. The silicon oil method was investigated and gave higher SSCs than the modified fluorescence method. Further studies on the mechanism of norfloxacin accumulation by M. aurum were performed. An increase in the pH of the wash buffer from 7.0 to 9.0 did not significantly affect the final SSC obtained. Accumulation was nonsaturated over a norfloxacin concentration range of 0 to 100 microg/ml, and the proton motive force inhibitor 2,4-dinitrophenol (1 and 2 mM), whether it was added before or after norfloxacin was added, had no effect on the final SSC obtained. 2,4-Dinitrophenol also had no effect on norfloxacin accumulation by M. smegmatis. Furthermore, norfloxacin accumulation by M. aurum was unaffected by the presence of either Tween 80 or subinhibitory concentrations of ethambutol in the growth medium. Therefore, it is proposed that norfloxacin accumulation by mycobacteria occurs by simple, energy-independent diffusion.


[EFFECTIVENESS OF DIGITAL CUSTOMIZED STEEL PLATE IN TREATMENT OF COMPLEX FRACTURES OF LIMBS].
To observe the effectiveness of digital customized plate in the treatment of complex limb fracture. Between January 2012 and May 2013, CT raw data of complex limb fracture were used to establish the fracture three-dimensional simulation model after reduction, and a customized personalized anatomic plate was designed and used for internal fixation after open reduction in 42 cases. There were 22 males and 20 females, aged 16-53 years (average, 37.4 years). The causes of injury were traffic accident in 21 cases, falling from height in 18 cases, crush by heavy objects in 3 cases, including 26 cases of fresh closed fracture and 16 cases of open fracture (9 cases of type I and 7 cases of type II according to Gustilo classification). According to AO classification, there were 15 cases of humerus comminuted fracture, 4 cases of radial comminuted fracture, 8 cases of femoral comminuted fracture, and 15 cases of tibia comminuted fracture. The interval of injury and operation was 6-28 days (mean, 10 days). Reduction and internal fixation of fracture were successfully performed on 42 patients. The length and position of digital customized plate, direction and length of screw implant, number of screw were basically identical with preoperative design. The operation time was 35-120 minutes (mean, 70 minutes); the blood loss volume was 30-500 mL (mean, 180 mL); and X ray fluoroscopy frequency was 2-6 times (mean, 3 times). Superficial infection occurred in 2 cases, and was cured after dressing change; primary healing of incision was obtained in the other patients. Forty-two cases were followed up 6-24 months with an average of 11.5 months. The fracture healing time was 8-19 weeks (mean, 14 weeks) in 41 cases; delayed union occurred in 1 case at 44 weeks after operation. The fracture anatomical reduction was achieved in 19 cases, malunion in 3 cases, and functional reduction in the other patients. At last follow-up, no plate and screw loosening and breakage was observed. Digital customized plate in treatment of complex fractures of limbs, especially for the multiple comminuted fracture of long bones of the limbs has the advantages of convenient operation, less trauma, fewer complications, and good effectiveness.


Through 40,000 years of human presence in Southern Europe: the Italian case study.
The Italian Peninsula, a natural pier across the Mediterranean Sea, witnessed intricate population events since the very beginning of the human occupation in Europe. In the last few years, an increasing number of modern and ancient genomes from the area have been published by the international research community. This genomic perspective started unveiling the relevance of Italy to understand the post-Last Glacial Maximum (LGM) re-peopling of Europe, the earlier phase of the Neolithic westward migrations, and its linking role between Eastern and Western Mediterranean areas after the Iron Age. However, many open questions are still waiting for more data to be addressed in full. With this review, we summarize the current knowledge emerging from the available ancient Italian individuals and, by re-analysing them all at once, we try to shed light on the avenues future research in the area should cover. In particular, open questions concern (1) the fate of pre-Villabruna Europeans and to what extent their genomic components were absorbed by the post-LGM hunter-gatherers; (2) the role of Sicily and Sardinia before LGM; (3) to what degree the documented genetic structure within the Early Neolithic settlers can be described as two separate migrations; (4) what are the population events behind the marked presence of an Iranian Neolithic-like component in Bronze Age and Iron Age Italian and Southern European samples.


Congenital Ptosis Associated With Adduction as a Dysinnervation Disorder: A Report of a Rare Case.
The levator palpebrae superioris is the primary muscle responsible for elevation of the eyelid. This muscle is innervated by the third intracranial nerve. Any pathology affecting the muscle or the supplying nerve can lead to blepharoptosis. In this study, we share our experience of a two-year-old baby boy patient who presented with a rare congenital disorder manifested as blepharoptosis increased with adduction bilaterally with no limitation of ocular muscles action except bilateral underaction of inferior oblique muscles. To our knowledge, this unusual presentation has not been previously reported in the literature. We aim in this report to build more knowledge on such a rare clinical presentation. Based on the findings, this could be a case of congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorders (CCDDs). CCDDs/CID is a group of conditions that includes blepharoptosis as part of their clinical presentation. This group of conditions includes Duane's retraction syndrome, congenital fibrosis of extraocular muscles, and monocular elevation defect.


Reactive-site-centric chemoproteomics identifies a distinct class of deubiquitinase enzymes.
Activity-based probes (ABPs) are widely used to monitor the activity of enzyme families in biological systems. Inferring enzyme activity from probe reactivity requires that the probe reacts with the enzyme at its active site; however, probe-labeling sites are rarely verified. Here we present an enhanced chemoproteomic approach to evaluate the activity and probe reactivity of deubiquitinase enzymes, using bioorthogonally tagged ABPs and a sequential on-bead digestion protocol to enhance the identification of probe-labeling sites. We confirm probe labeling of deubiquitinase catalytic Cys residues and reveal unexpected labeling of deubiquitinases on non-catalytic Cys residues and of non-deubiquitinase proteins. In doing so, we identify ZUFSP (ZUP1) as a previously unannotated deubiquitinase with high selectivity toward cleaving K63-linked chains. ZUFSP interacts with and modulates ubiquitination of the replication protein A (RPA) complex. Our reactive-site-centric chemoproteomics method is broadly applicable for identifying the reaction sites of covalent molecules, which may expand our understanding of enzymatic mechanisms.


Sequence of 1060 3'-terminal nucleotides of poliovirus RNA as determined by a modification of the dideoxynucleotide method.
The dideoxynucleotide method for sequencing DNA developed by Sanger et al. [Sanger, F., Nicklen, S. & Coulson, A. (1977) Proc. Natl. Acad. Sci. USA 74, 5463-5467] was modified to allow sequence analysis of poliovirus RNA without recourse to cloning. Our method involves reverse transcription of poliovirus RNA followed by cDNA-dependent DNA synthesis in the presence of unlabeled dNTPs and 2',3'-dideoxynucleoside triphosphates, with Escherichia coli DNA polymerase I (Klenow) used to catalyze the reaction. DNA synthesis is primed by 5'-32P-labeled RNase T1- or RNase A-resistant oligonucleotides generated from poliovirus RNA. The sequence of 1060 nucleotides preceding the 3'-terminal poly(A) is presented. Based on the position of termination codons we propose that viral translation terminates at nucleotide -562.


Role of hydrogen bonding on the self-organization of phenyleneethynylenes on surfaces.
A series of carboxylic acid substituted phenyleneethynylenes, having a rigid backbone of 2.7 ± 0.1 nm, were synthesized by following the Heck-Cassar-Sonagashira-Hagihara cross-coupling reaction. Hydrogen bonding, through the formation of cyclic dimers of carboxylic acid, is more preferred over catemeric structures in all the molecular systems under investigation. The formation of extended two-dimensional patterns on highly oriented pyrolitic graphite (HOPG) surface is dictated by the position as well as number of the carboxylic acid groups on the phenyleneethynylenes. Highly ordered extended arrangements, in the linear and stepwise fashion, were observed when the carboxylic acid groups are attached in the para and meta positions of phenyleneethynylenes. The vital role of the number of carboxylic acid on the organization of molecules is evident in the case of tetracarboxylic acid derivative wherein a Kagome-type structure was observed. Further, the coassembly of two types of phenyleneethynylenes was achieved on HOPG surface through acid base interaction.


Spermiogenesis and Sperm Structure in Relation to Early Events of Fertilization in the Limpet Tectura testudinalis (Muller, 1776).
Spermiogenesis and fertilization in the limpet Tectura testudinalis (Mollusca: Archaeogastropoda: Patelloidea) were examined using scanning and transmission electron microscopy, as well as light microscopy. Spermiogenesis was similar to that described for other Lottiidae (Patelloidea), but some key differences were noted. We observed that the acrosomal vesicle forms on the plasma membrane from several Golgi-derived proacrosomal vesicles during the early spermatid. Evidence from anti-actin antibody staining of a related species, T. scutum, indicates that the acrosome probably contains G-actin in three different locations, but there are no preformed actin filaments. The flagellum of mature sperm tapers to a thin, filamentous end-piece. The mature egg of T. testudinalis is enclosed by a thin vitelline layer and a thick jelly coat bound by follicle cells. Where a mature sperm encounters the intact jelly coat, its acrosome tip may elongate, up to twice its original length. The acrosome reaction is not induced, but by this mechanism the acrosome bridges the jelly coat and extends down far enough to contact the vitelline layer. During the elongation of the acrosome, microfilaments are formed inside the tip. As well, new membrane required for this process is supplied by elimination of any slack in the plasma membrane and also perhaps by spontaneous formation of vesicles inside the acrosome. Once the tip of the sperm contacts and binds with the vitelline layer it undergoes the acrosome reaction, in which the plasma and acrosomal membranes fuse and roll back in a manner typical of scaphopods and some polychaetes. Sperm also may bind directly with the vitelline layer when the jelly coat is absent. Furthermore, the acrosome tip may undergo spontaneous fusion with a naked egg microvillus that formerly connected with a follicle cell process. Thus, the sperm either individually or collectively are equipped to deal with any one of several potential routes to successful fertilization of the egg. Current theories of gastropod phylogeny place the limpets as basal to the Gastropoda, but new evidence presented here supports the idea that they are a divergent group, with some unique innovations in sperm design.


Rescuing the physician-scientist workforce: the time for action is now.
The 2014 NIH Physician-Scientist Workforce (PSW) Working Group report identified distressing trends among the small proportion of physicians who consider research to be their primary occupation. If unchecked, these trends will lead to a steep decline in the size of the workforce. They include high rates of attrition among young investigators, failure to maintain a robust and diverse pipeline, and a marked increase in the average age of physician-scientists, as older investigators have chosen to continue working and too few younger investigators have entered the workforce to replace them when they eventually retire. While the policy debates continue, here we propose four actions that can be implemented now. These include applying lessons from the MD-PhD training experience to postgraduate training, shortening the time to independence by at least 5 years, achieving greater diversity and numbers in training programs, and establishing Physician-Scientist Career Development offices at medical centers and universities. Rather than waiting for the federal government to solve our problems, we urge the academic community to address these goals by partnering with the NIH and national clinical specialty and medical organizations.


Medical school attended as a predictor of medical malpractice claims.
Following earlier research which showed that certain types of physicians are more likely to be sued for malpractice, this study explored (1). whether graduates of certain medical schools have consistently higher rates of lawsuits against them, (2). if the rates of lawsuits against physicians are associated with their school of graduation, and (3). whether the characteristics of the medical school explain any differences found. Retrospective analysis of malpractice claims data from three states merged with physician data from the AMA Masterfile (n=30288). All US medical schools with at least 5% of graduates practising in three study states (n=89). Proportion of graduates from a medical school for a particular decade sued for medical malpractice between 1990 and 1997 and odds ratio for lawsuits against physicians from high and low outlier schools; correlations between the lawsuit rates of successive cohorts of graduates of specific medical schools. Medical schools that are outliers for malpractice lawsuits against their graduates in one decade are likely to retain their outlier status in the subsequent decade. In addition, outlier status of a physician's medical school in the decade before his or her graduation is predictive of that physician's malpractice claims experience (p<0.01). All correlations of cohorts were relatively high and all were statistically significant at p<0.001. Comparison of outlier and non-outlier schools showed that some differences exist in school ownership (p<0.05), years since established (p<0.05), and mean number of residents and fellows (p<0.01). Consistent differences in malpractice experience exist among medical schools. Further research exploring alternative explanations for these differences needs to be conducted.


Inhibitory Effects of Novel SphK2 Inhibitors on Migration of Cancer Cells.
Cell migration is an essential process for survival and differentiation of mammalian cells. Numerous diseases are induced or influenced by inappropriate regulation of cell migration, which plays a key role in cancer cell metastasis. In fact, very few anti-metastasis drugs are available on the market. SphKs are enzymes that convert sphingosine to sphingosine-1-phosphate (S1P) and are known to control various cellular functions, including migration of cells. In human, SphK2 is known to promote apoptosis, suppresses cell growth, and controls cell migration; in addition, the specific ablation of SphK2 activity was reported to inhibit cancer cell metastasis. The previously identified SG12 and SG14 are synthetic analogs of sphingoid and can specifically inhibit the functions of SphK2. We investigated the effects of the SphK2 specific inhibitors on the migratory behavior of cells. We investigated how SG12 and SG14 affect cell migration by monitoring both cumulative and individual cell migration behavior using HeLa cells. SG12 and SG14 mutually showed stronger inhibitory effects with less cytotoxicity compared with a general SphK inhibitor, N,N-dimethylsphingosine (DMS). The mechanistic aspects of specific SphK2 inhibition were studied by examining actin filamentation and the expression levels of motility-related genes. The data revealed that SG12 and SG14 resemble DMS in decreasing overall cell motility, but differ in that they differentially affect motility parameters and motility-related signal transduction pathways and therefore actin polymerization, which are not altered by DMS. Our findings show that SphK2 inhibitors are putative candidates for anti-metastatic drugs.


Congenital second branchial cleft anomalies in children: A report of 52 surgical cases, with emphasis on characteristic CT findings.
The objectives of this study was to review the clinical features and surgical treatment outcomes of congenital second branchial cleft anomalies (CSBCAs) and to investigate the characteristic computed tomography (CT) findings of CSBCAs. We conducted a retrospective study of 52 children who were referred to Shanghai Children's Hospital from October 2014 to December 2021 diagnosed as CSBCAs. There were 36 males and 16 females. Of them, 35 patients were presented as having a skin pit at birth or discharge from the skin opening on the lateral neck, and 17 patients presented with an asymptomatic or painful mass. The typical CT features of CSBCAs included isolated and homogeneously hypodense cystic lesions surrounded by a uniformly thin, smooth wall. CSBCAs were generally located at the anteromedial border of the sternocleidomastoid muscle, posterior to the submandibular gland, and lateral to the carotid sheath. All patients were treated surgically and only one case underwent ipsilateral tonsillectomy. After a median follow-up of 30 (range 4-90) months, no recurrence or complications were observed. The CSBCAs show some characteristic CT findings, which can help clinicians diagnose and plan surgical strategies. High ligation of the lesions is sufficient for complete excision of CSBCAs.


Antenatal diagnosis of haemoglobinopathies by Biorex chromatography of haemoglobin.
Biorex chromatograhpy of haemoglobin has been compared to the standard chromatographic separation of radioactive globin chains in 60 fetal blood samples obtained for the antenatal diagnosis of haemoglobinopathies. Biorex chromatography of haemoglobin permitted two measurements, the optical density at 418 nm and the radioactivity incorporated into fetal and adult haemoglobin. The two measurements were highly correlated (r2=0.96) and enabled a distinction between homozygous from heterozygous states of the diseases to be made, particularly in beta thalassaemia. A single column was used for 50 analyses. This fast and very sensitive method is proposed for the antenatal diagnosis of haemoglobinopathies using fetal blood.


Behavioral effects of prenatal exposure to ethylene dibromide.
Pregnant female Long-Evans hooded rats were exposed to 0, 0.43, 6.67, or 66.67 ppm ethylene dibromide (EDB) via inhalation for four hours/day three days/week from Day 3 to Day 20 of gestation. The 66.67 ppm dose produced an increase in defecation during exposure, decreased gestational weight gain, and enhanced rotorod performance and T-maze brightness discrimination acquisition in the offspring. Similar changes were noted in the dams and offspring exposed to 6.67 ppm, but the magnitude of the effects was reduced. No effects of exposure to 0.43 ppm were detected, nor were litter size, litter composition, nest building, pup retrieval, DRL-20 acquisition, straight alley running speed, or passive avoidance affected by exposure to any dose. We suggest that the behavioral effects of the medium and high doses may be secondary to stress reactions in the dams to exposure to these doses.


Non-expert use of quantitative EEG displays for seizure identification in the adult neuro-intensive care unit.
Video-EEG monitoring is the ultimate way to diagnose non-convulsive status epilepticus (NCSE) in intensive care units (ICU). Usually EEG recordings are evaluated once a day by an electrophysiologist, which may lead to delay in diagnosis. Digital EEG trend analysis methods like amplitude integrated EEG (aEEG) and density spectral array (DSA) have been developed to facilitate recognition of seizures. In this study, we aimed to investigate the diagnostic utility of these methods by non-expert physicians and ICU nurses for NCSE identification in an adult neurological ICU. Ten patients with NCSE and ten control patients without seizures were included in the study. The raw EEG recordings of all subjects were converted to both aEEG and DSA and displayed simultaneously without conventional EEG. After training for seizure recognition with both methods, two physicians and two nurses analyzed the visual displays individually, and marked seizure timings. Their results were compared with those of a study epileptologist. Participants analyzed 615h of EEG data with 700 seizures. Overall, 63% of the seizures were recognized by all, 15.6% by three, 11.6% by two, 8.3% by one rater and only 1.5% were missed by all of them (sensitivity was 88-99%, and specificity was 89-95% when the ratings were assessed as 1-h epochs). False positive rates were 1 per 2h in the study and 1 per 6h in the control groups. Interrater agreement was high (κ=0.79-0.81). Bilateral independent seizures and ictal recordings with lower amplitude and shorter duration were more likely to be missed. There was no difference in performance between the rating of physicians and nurses. Our study demonstrates that bedside nurses, ICU fellows and residents can achieve acceptable level of accuracy for seizure identification using the digital EEG trend analysis methods following brief training. This may help earlier notification of the electrophysiologist who is not always available in ICUs.


The need for global certification in the field of health informatics: some ethical issues.
In the past, the training of health information professionals (HIPs) has focussed almost exclusively on technical matters, the concerns of software developers and purveyors have essentially centred on security and functionality, and health care providers have mainly worried about costs and efficiency. This paper outlines some ethical threats that are ignored by such a purely technical focus and argues that because of the increasing globalization of health care delivery through e-Health, and because of the international threats to confidentiality posed by legislation such as the US Patriot Act, the health informatics community should pursue a project of global certification for HIPs that includes information ethics as an integral component. It also argues that a corresponding certification process for health care institutions and software developers should be initiated.


Estimation of fetal weight by external abdominal measurements.
In 2108 pregnant women, external abdominal measurements were correlated to the weight of the newborn child. The product of girth and uterine height was more closely correlated to the infant weight than were any of these maternal variables alone or in other combinations, but the accuracy of this method was almost as low as of simple external palpation. For successive estimations of fetal growth the product of maternal girth and uterine height may be more adequate than either of these variables alone.


Frequency, microbial interactions, and antimicrobial susceptibility of Fusobacterium nucleatum and Fusobacterium necrophorum isolated from primary endodontic infections.
This study assessed the prevalence and microbial interactions of Fusobacterium nucleatum and Fusobacterium necrophorum in primary endodontic infections from a Brazilian population and their antimicrobial susceptibility to some antibiotics by the E-test. One hundred ten samples from infected teeth with periapical pathologies were analyzed by culture methods. Five hundred eighty individual strains were isolated; 81.4% were strict anaerobes. F. nucleatum was found in 38 root canals and was associated with Porphyromonas gingivalis, Prevotella spp., and Eubacterium spp. F. necrophorum was found in 20 root canals and was associated with Peptostreptococcus prevotii. The simultaneous presence of F. nucleatum and F. necrophorum was not related to endodontic symptoms (p > 0.05). They were 100% susceptible to amoxicillin, amoxicillin/clavulanate, and cephaclor. Fusobacterium spp. is frequently isolated from primary-infected root canals of teeth with periapical pathologies. Amoxicillin is a useful antibiotic against F. nucleatum and F. necrophorum in endodontic infections and has been prescribed as the first choice in Brazil.


Characterizing Physicians Practice Phenotype from Unstructured Electronic Health Records.
Clinical practice varies among physicians in ways that could lead to variation in what is documented in a patient's electronic health records (EHR) and act as a source of bias to predictive model performance that is independent of patient health status. We used EHR encounter note data on 5,187primary care patients 50 to 85 years of age selected for a separate case-control study covering 144 unique primary care physicians (PCPs). A validated text extractor tool was used to identify mentions of Framingham heartfailure signs and symptoms (FHFSS) from the notes. Hierarchical clustering analyses were performed on the encounter note data for finding subgroups of PCPs with distinct FHFSS documentation behaviors. Three distinct PCP groups were identified that differed in the rate of documenting assertions and denials of mentions. Physician subgroup differences were not explained by patient disease burden, medication use, or other factors related to health.


Synthesis and properties of [A19-(p-fluorophenylalanine)] insulin.
The synthesis of [Phe(F)A19]insulin (porcine) is described. First the protected [Phe(F)19]A-chain was assembled by segment condensation of [1-12] and [13-21] using the dicyclohexyldiimide/1-hydroxybenzotriazole procedure. [Phe(F)19]A-chain was purified by ion exchange chromatography after removal of all the protecting groups (Boc, But, OBut and S-Trt) and its conversion into the tetra-S-sulfonated derivative. [Phe(F)A19]insulin was prepared by combination with porcine B-chain and purified by gel filtration and ion-exchange chromatography. The in vitro biological activity of this analogue was 60%. CD spectra in the near and far UV are qualitatively very similar to those of insulin.


Off-Stream Watering Systems and Partial Barriers as a Strategy to Maximize Cattle Production and Minimize Time Spent in the Riparian Area.
A study was conducted in 2009 at two locations in Manitoba (Killarney and Souris), Canada to determine the impact of off-stream waterers (OSW) with or without natural barriers on (i) amount of time cattle spent in the 10 m buffer created within the riparian area, referred to as the riparian polygon (RP), (ii) watering location (OSW or stream), and (iii) animal performance measured as weight gain. This study was divided into three 28-day periods over the grazing season. At each location, the pasture-which ranged from 21.0 ha to 39.2 ha in size-was divided into three treatments: no OSW nor barriers (1CONT), OSW with barriers along the stream bank to deter cattle from watering at the stream (2BARR), and OSW without barriers (3NOBARR). Cattle in 2BARR spent less time in the RP in Periods 1 (p = 0.0002), 2 (p = 0.1116), and 3 (p < 0.0001) at the Killarney site compared to cattle in 3NOBARR at the same site. Cattle in 2BARR at the Souris site spent more time in the RP in Period 1 (p < 0.0001) and less time in Period 2 (p = 0.0002) compared to cattle in 3NOBARR. Cattle did use the OSW, but not exclusively, as watering at the stream was still observed. The observed inconsistency in the effectiveness of the natural barriers on deterring cattle from the riparian area between periods and locations may be partly attributable to the environmental conditions present during this field trial as well as difference in pasture size and the ability of the established barriers to deter cattle from using the stream as a water source. Treatment had no significant effect (p > 0.05) on cow and calf weights averaged over the summer period. These results indicate that the presence of an OSW does not create significant differences in animal performance when used in extensive pasture scenarios such as those studied within the present study. Whereas the barriers did not consistently discourage watering at the stream, the results provide some indication of the efficacy of the OSW as well as the natural barriers on deterring cattle from the riparian area.


Intention retrieval and deactivation following an acute psychosocial stressor.
We often form intentions but have to postpone them until the appropriate situation for retrieval and execution has come, an ability also referred to as event-based prospective memory. After intention completion, our cognitive system has to deactivate no-more-relevant intention representations from memory to avoid interference with subsequent tasks. In everyday life, we frequently rely on these abilities also in stressful situations. Surprisingly, little is known about potential stress effects on these functions. Therefore, the present study aimed to examine the reliability of event-based prospective memory and of intention deactivation in conditions of acute psychosocial stress. To this aim, eighty-two participants underwent the Trier Social Stress Test, a standardized stress protocol, or a standardized control situation. Following this treatment, participants performed a computerized event-based prospective memory task with non-salient and focal prospective memory cues in order to assess prospective memory performance and deactivation of completed intentions. Although the stress group showed elevated levels of salivary cortisol as marker of a stress-related increase in hypothalamus-pituitary-adrenal axis activity throughout the cognitive testing period compared to the no-stress group, prospective memory performance and deactivation of completed intentions did not differ between groups. Findings indicate that cognitive control processes subserving intention retrieval and deactivation after completion may be mostly preserved even under conditions of acute stress.


Business intelligence: using insight to improve the value and performance of your practice.
Using information to improve the value of your practice can be a great way to create leverage and improve the performance of your practice. Business intelligence (BI) is the result of a complete system that produces meaningful insights by providing the information necessary to make business decisions. Changes made from these insights improve both the performance and value of your practice. It is important to identify the key elements required of a good BI system and the areas within a practice that can directly benefit from an effective BI system.


High polyunsaturated fatty acid, thromboxane A2, and alpha-fetoprotein concentrations at the human feto-maternal interface.
Polyunsaturated fatty acids (PUFA) like arachidonic (C20:4) and docosahexaenoic (C22:6) acids are essential for harmonious fetal development. This study evaluates, at near term, the distributions of free fatty acids (FFA) and their fetal carrier protein, alpha-fetoprotein (AFP) in the maternal (M) and fetal circulation (umbilical arteries (A) and vein (V)), focusing on the feto-material interface where maternal intervillous blood (I) contacts the fetal trophoblast. FFA concentrations in intervillous and maternal blood were similar, while those in umbilical arteries and vein were 2- to 4-fold lower (P < 0.001). There were more saturated FFA in umbilical vein (41%) and arteries (44%) blood than in maternal (30%) and intervillous (32%) blood (P < 0.001). Monounsaturated FFA predominated (P < 0.001) in maternal (43%) blood, but not in intervillous (35%), umbilical vein (33%) and arteries (31%) blood. Di-triunsaturated FFA were similar in intervillous and maternal (25%) blood and lower in umbilical vein and arteries (16%) (P < 0.001). PUFA were low in maternal (2.5%) blood and higher in intervillous and umbilical vein and arteries (9%, P < 0.001); consequently, C20:4 (40 microM) and C22:6 (16 microM) were the most abundant in the intervillous space. The AFP concentrations and AFP lectin-reactive isoforms were similar in intervillous and umbilical vein and arteries blood, but immuno-electrophoresis revealed a particular AFP conformation (less immuno-reactive, more anionic) in the intervillous space, suggesting that AFP is heavily loaded with PUFA at the feto-maternal interface. Prostacyclin derived from C20:4 was similar in all compartments but the thromboxane A2 concentration was 10-fold higher in intervillous blood than in maternal and umbilical vein and arteries blood. Thus the feto-maternal interface has a specific pattern of cell signalling molecules that might critically influence parturition.


Effects of Abutment Removal and Reconnection on Inflammatory Cytokine Production Around Dental Implants.
The purpose of this study was to examine effects of abutment change on inflammatory cytokine production around implants. Ten partially edentulous patients with a mean age of 60 years were recruited and divided into 2 groups. External Brånemark implants with anodic oxidized surface were installed and submerged in all patients. In the control group, the healing abutments were delivered at the second surgery, and they were removed more than 3 times till the final prosthesis delivery. In the test group, the final abutments were delivered at the second surgery. At different time points during the treatment, periimplant crevicular fluid was collected, and proinflammatory cytokines (interleukin-1β [IL-1β] and tumor necrosis factor [TNF]-α) were measured with enzyme-linked immunosorbent assay. The bone level was measured on the radiograms and clinical indices were also taken. All implants were osseointegrated. In the test group, IL-1β level and probing depths were less in test group patients compared with the control group patients, whereas TNF-α level and bone level were not different between the groups. Although TNF-α and bone levels were not significantly different, delivering final abutment at the second surgery would induce less inflammation in the tissues around the implant.


Interactions of metronidazole and chloramphenicol with myoglobin: Crystal structure of a Mb-acetamide product.
Nitroorganics present a general concern for a safe environment due to their health hazards. However, some nitroorganics such as metronidazole (Mtz) and chloramphenicol (CAM) also possess medicinal value. Mtz and CAM can undergo reductive bioactivation presumably via their nitroso derivatives. We show, using UV-vis spectroscopy, that sperm whale myoglobin (swMb) and its distal pocket mutants retaining H-bonding capacity react with Mtz in the presence of dithionite to generate products with spectra suggestive of the Fe-bound nitroso (Fe-RNO; λmax ~420 nm) forms. We have crystallized and solved the X-ray crystal structure of an H64Q swMb-acetamide compound to 1.76 Å resolution; formation of this compound results from the serendipitous crystallographic trapping, by the heme center, of acetamide from the reductive decomposition of Mtz. Only one of the swMb proteins, namely H64Q swMb with a relatively flexible Gln64 residue, reacted with CAM presumably due to the bulky nature of CAM that generally may restrict its access to the heme site.


Maternal near-misses at a provincial hospital in Papua New Guinea: A prospective observational study.
Maternal near-miss indices are World Health Organisation (WHO) recognised indicators that may improve our understanding of factors associated with maternal morbidity and mortality. In Papua New Guinea (PNG) where maternal mortality is among the highest in the world, only one study has documented near-miss indices in a tertiary-level hospital, but none from provincial hospitals where the majority of under-privileged women access healthcare services. To determine the near-miss ratio, maternal mortality index (MMI), and associated maternal indices for Modilon Hospital in Madang Province of PNG. All women attending Modilon Hospital who met the WHO maternal near-miss definition and/or a WHO-modified (PNG-specific) near-miss definition, were prospectively enrolled. There were 6019 live births during the audit period; 163 women presented with life-threatening conditions (153 near-misses and 10 maternal deaths). The maternal near-miss ratio was 25.4/1000 live births and the maternal mortality ratio (MMR) was 166/100 000 live births, with a maternal death to near-miss ratio of 1:15.3. The severe maternal outcome ratio was 27.1/1000 live births and the total mortality index was 6.8%. Higher proportions of near-miss women were aged ≥30 years, nulliparous, illiterate, from rural communities, lacked formal employment, referred from peripheral health facilities, unbooked, had history of still births and were anaemic. Sociodemographic factors such as women's rights, education level and status in society, in addition to appropriate health reforms with greater financial and political support are urgently needed to ensure underprivileged women in rural PNG have access to family planning, supervised deliveries and skilled emergency obstetric care.


Three-dimensional multislice helical computed tomography techniques for canine extra-hepatic portosystemic shunt assessment.
The purpose of the present study was to investigate the feasibility and usefulness of three-dimensional (3D) multislice computed tomography (CT) angiography with maximum intensity projection (MIP) and volume rendering (VR) in six dogs with clinical and sonographic findings suggestive of portosystemic shunt. Furthermore, we aimed to estimate the diameter of the portal vein and shunt vessels. MIP and VR reconstructions were performed for each patient and the origin and insertion of all shunt vessels were detected. In addition, 3D reconstructions allowed excellent depiction of vascular morphology and topography. All diagnoses and vessel measurements were confirmed by surgery. 3D multidetector CT angiography is a promising, noninvasive, and accurate method of evaluating dogs with suspected portosystemic shunts.


The potential health gain and cost savings of improving adherence in chronic myeloid leukemia.
Healthcare costs are rising due to an increase in chronic diseases, including chronic myeloid leukemia (CML) due to improved survival. In CML care, patient adherence and physician adherence are key elements. We assessed the potential health gain and cost savings when both are improved, using a decision analytic model that integrated various sources of evidence. The current situation was compared to a theoretical situation in which either patient or physician adherence is improved, in terms of costs and quality-adjusted life years (QALYs). Current patient adherence rate is 74%, improvement to 100% resulted in 0.1031 QALYs gained and a saving of €17,509 per patient over a 25-year period. Improving physician adherence from 72% to 100%, resulted in 0.0380 QALYs and €7606. Enhancement of either adherence results in substantial health gain and cost savings. Regarding the rising healthcare costs, new strategies should focus on improving adherence to keep healthcare affordable in the future.


Polyserositis in pigs due to generalized Escherichia coli infection.
A fibrinous polyserositis syndrome due to generalized Escherichia coli infection in pigs was observed in 13 out of 17 systematically monitored herds. The mortality rate was approximately 0.1% among liveborn pigs. The occurrence was usually sporadic but a minor enzootic was observed in one herd. Most of the affected pigs succumbed during first or second week of life but cases were observed throughout the suckling period. The clinical signs included marked depression, anorexia, rough haircoat, laboured respiration and death in two to five days. Predominant gross pathological lesions were signs of septicaemia and a voluminous, gelatinous and fibrinous exudate in the pleural, the pericardial and the peritoneal cavities. Frequently also a firbinous polyarthritis and a fibrinous pneumonia were present. The majority of the isolated invasive E. coli strains were nonhaemolytic. Serologically 11 different E. coli O groups were encountered. O group most frequently represented was 020. None of the examined E. coli strains belonged to the serogroups which frequently are associated with enteropathogenicity in pigs.


Soft-Tissue Chondroma in the Preauricular Region: An Unusual Presentation.
Chondroma is a benign cartilaginous tumor composed of mature hyaline cartilage and represents only 2.38% of all osteocartilaginous tumors; cases that arise in the preauricular region are rarely found in the literature. This article presents an 80-year-old man with preauricular swelling on the right side and pain with no limitation of joint motion. This patient was evaluated by preoperative clinical manifestation, fine needle aspiration, ultrasound, and magnetic resonance imaging (MRI) scans. The MRI shows a solid lobulated lesion between the masseter muscle and the parotid gland whereas fine-needle aspiration did not provide a diagnosis. Based on these images and the patient's indications and symptoms, a surgical intervention was performed. It is possible to identify three different types of chondromas in the parotid region based on their location. Among the cases of chondroma in the literature, only six originating in the soft tissue of the parotid region have been reported, including this one.


Molecular chaperones and hypoxic-ischemic encephalopathy.
Hypoxic-ischemic encephalopathy (HIE) is a disease that occurs when the brain is subjected to hypoxia, resulting in neuronal death and neurological deficits, with a poor prognosis. The mechanisms underlying hypoxic-ischemic brain injury include excitatory amino acid release, cellular proteolysis, reactive oxygen species generation, nitric oxide synthesis, and inflammation. The molecular and cellular changes in HIE include protein misfolding, aggregation, and destruction of organelles. The apoptotic pathways activated by ischemia and hypoxia include the mitochondrial pathway, the extrinsic Fas receptor pathway, and the endoplasmic reticulum stress-induced pathway. Numerous treatments for hypoxic-ischemic brain injury caused by HIE have been developed over the last half century. Hypothermia, xenon gas treatment, the use of melatonin and erythropoietin, and hypoxic-ischemic preconditioning have proven effective in HIE patients. Molecular chaperones are proteins ubiquitously present in both prokaryotes and eukaryotes. A large number of molecular chaperones are induced after brain ischemia and hypoxia, among which the heat shock proteins are the most important. Heat shock proteins not only maintain protein homeostasis; they also exert anti-apoptotic effects. Heat shock proteins maintain protein homeostasis by helping to transport proteins to their target destinations, assisting in the proper folding of newly synthesized polypeptides, regulating the degradation of misfolded proteins, inhibiting the aggregation of proteins, and by controlling the refolding of misfolded proteins. In addition, heat shock proteins exert anti-apoptotic effects by interacting with various signaling pathways to block the activation of downstream effectors in numerous apoptotic pathways, including the intrinsic pathway, the endoplasmic reticulum-stress mediated pathway and the extrinsic Fas receptor pathway. Molecular chaperones play a key role in neuroprotection in HIE. In this review, we provide an overview of the mechanisms of HIE and discuss the various treatment strategies. Given their critical role in the disease, molecular chaperones are promising therapeutic targets for HIE.


Less tachycardia during transnasal versus conventional gastroscopy.
Transnasal endoscopy is well tolerated, but physiological benefits compared with conventional gastroscopy have not been studied in detail. The aims of this randomised study were to evaluate cardiopulmonary features, patient tolerance, and the endoscopist's evaluation of transnasal versus conventional endoscopy. Patients were randomized to either a conventionally sized transoral (50 patients) or to a transnasal endoscopy (48 patients). Pulse rate and oxygen saturation were registered as well as the patient's tolerance and the endoscopist's evaluation of the procedure. The success rate for transnasal gastroscopy was 77%, mainly because of nasal stenosis. The per- and post-endoscopy pulse rates of the conventional group were elevated compared with those of the transnasal group (p = 0.04 and p = 0.02). Procedural discomfort in the two groups was similar, but significantly fewer transnasal patients reported gagging (p < 0.01). The endoscopists evaluated the technical features as good even if they did not reach those of conventional gastroscopy (p < 0.05). In this study, transnasal gastroscopy was technically inferior to conventional gastroscopy. There was no benefit in terms of patient comfort, except for less gagging. A lower stress response was indicated by significantly lower pulse rates during transnasal than during conventional gastroscopy, but the clinical relevance of this finding needs to be further investigated.


Driving arginine catabolism to activate systemic autophagy.
Macroautophagy/autophagy is a conserved cellular self-digestive mechanism to catabolize superfluous or damaged cellular components to maintain cell homeostasis. Impaired autophagy underlies multiple pathophysiological states, including aging, neurodegenerative, inflammatory, and metabolic diseases. Intermittent fasting and caloric restriction are effective means by which to activate autophagy, yet relatively few people can sustain such intensive interventions in real-world settings. Moreover, current pharmacotherapies do not yet fully exploit autophagic flux as a target mechanism. Here, we discuss recent work, which demonstrates that arginine catabolism is a tractable process to activate autophagy with utility to treat obesity and its complications. Hepatocyte-specific transgenic activation of arginine catabolism, or systemic administration of an anti-tumor pharmacotherapy, pegylated arginine deiminase, each promote energy expenditure and insulin sensitivity, and reduce dyslipidemia and hepatic steatosis in obese mice. These effects depend upon hepatocyte Fgf21, and whole-body Becn1 expression. The data suggest that hepatocyte and systemic arginine catabolism drive autophagy, and identify an index pharmacological agent to leverage this process.


[X-ray computed tomography in surveillance of colorectal cancers treated by radical surgery].
This retrospective study covered 44 patients treated by abdominoperineal amputation (17 normal postoperative cases, 25 relapses, 2 abscesses) and 13 patients with disease recurrence after resection of a colorectal cancer. Twenty-nine of the 38 relapses occurred in less than two years. Recurrent lesions after abdominoperineal amputation (25 cases) were convex and generally larger than 3 cm in diameter; 13 of these lesions invaded contiguous structures. Endoscopic findings were positive for 11 of the 13 post-resection relapses whereas CT was positive in only 9 of the 13 cases (but included the 2 cases not diagnosed by endoscopy). 13 cases were punctured under CT guidance, but results were positive in only 11 cases. Endoscopy remains the first examination that should be performed for the follow-up of colic resections, but CT should be performed systematically when monitoring patients who have undergone abdominoperineal amputation.


Regulation of [3H]dopamine release from guinea pig striatum by NMDA receptor/channel activators and inhibitors.
Excitatory amino acids, that interact with the N-methyl-D-aspartate (NMDA) receptor stimulate release of [3H]dopamine [3H]DA) from the striatum of the guinea pig and rat in a concentration-dependent manner. DA release was measured in the presence of domperidone and nomifensine to avoid complications associated with autoreceptor alteration of and reuptake of released DA. This release is inhibited by magnesium. Therefore, all experiments were performed in the absence of this ion. The competitive NMDA antagonists D-(-)2-amino-5-phosphonopentanoic acid and 3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid and the noncompetitive antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine and phencyclidine also inhibit NMDA-stimulated release. Glycine enhances NMDA-stimulated release and can release [3H]DA in the absence of added NMDA. Release stimulated by glycine alone is not affected by 3-[(+-)-2-carboxypiperazine-4-yl]-propyl-1-phosphonic acid. Conversely, if the glycine antagonist 3-amino-1-hydroxy-2-pyrrolidone or 6-cyano-7-nitroquinoxaline-2,3-dione is included, NMDA elicits less release of [3H]DA. This inhibition can be overcome by increasing the concentration of glycine. The kappa-selective opioid agonist trans-(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide is also capable of inhibiting the NMDA-stimulated release of [3H]DA from guinea pig and rat striatum.(ABSTRACT TRUNCATED AT 250 WORDS)


Variation in the γ-glutamyltransferase 1 gene and risk of chronic pancreatitis.
Individuals with chronic pancreatitis are at increased risk for pancreatic cancer. We hypothesized that genetic variation in the γ-glutamyltransferase 1 (GGT1) gene, which was recently reported associated with pancreatic cancer risk in a genome-wide association study, is also associated with risk of chronic pancreatitis. Associations between common polymorphisms in GGT1 and chronic pancreatitis were evaluated using data and samples from the North American Pancreatitis Study 2. Patients (n = 496) and control subjects (n = 465) were genotyped for 4 single-nucleotide polymorphisms: rs4820599, rs2017869, rs8135987, and rs5751901. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) for chronic pancreatitis risk were calculated using multiple logistic regression models. Interactions with cigarette smoking and alcohol use were explored. Single-nucleotide polymorphisms rs8135987 and rs4820599 were both statistically significantly associated with risk of chronic pancreatitis; compared with common allele homozygotes, individuals with at least 1 minor allele were at increased risk (rs8135987: OR, 1.36; 95% CI, 1.03-1.80 [P(trend) = 0.01]; rs4820599: OR, 1.39; 95% CI, 1.04-1.84 [P(trend) = 0.0]; adjusted for age, sex, race, smoking status, and alcohol use). No significant interactions with cigarette smoking and alcohol use were observed. Our results suggest that common variation in the GGT1 gene may also affect risk of chronic pancreatitis.


Unraveling the luminescence signatures of chemical defects in polyethylene.
Chemical defects in polyethylene (PE) can deleteriously downgrade its electrical properties and performance. Although these defects usually leave spectroscopic signatures in terms of characteristic luminescence peaks, it is nontrivial to make unambiguous assignments of the peaks to specific defect types. In this work, we go beyond traditional density functional theory calculations to determine intra-defect state transition and charge recombination process derived emission and absorption energies in PE. By calculating the total energy differences of the neutral defect at excited and ground states, the emission energies from intra-defect state transition are obtained, reasonably explaining the photoluminescence peaks in PE. In order to study the luminescence emitted in charge recombination processes, we characterize PE defect levels in terms of thermodynamic and optical charge transition levels that involve total energy calculations of neutral and charged defects. Calculations are performed at several levels of theory including those involving (semi)local and hybrid electron exchange-correlation functionals, and many-body perturbation theory. With these critical elements, the emission energies are computed and further used to clarify and confirm the origins of the observed electroluminescence and thermoluminescence peaks.


Evolving role of bisphosphonates in women undergoing treatment for localized and advanced breast cancer.
Breast cancer commonly metastasizes to bone, producing hypercalcemia, pathologic fractures, spinal compression, and pain that increase morbidity and affect the patient's mobility and quality of life. The use of bisphosphonates like pamidronate and zoledronic acid inhibits osteolytic activity caused by bone metastases. The use of bisphosphonates to prevent bone loss and preserve bone health in the adjuvant setting in women with breast cancer undergoing hormonal therapy with aromatase inhibitors or ovarian suppression is being actively investigated. Interestingly, clodronate, an oral bisphosphonate, has been shown in 2 trials to decrease the risk of recurrence in women with early-stage breast cancer, suggesting a direct or indirect antitumor effect of bisphosphonates. Trials to confirm the antitumor effects of bisphosphonates are currently ongoing. Prolonged intravenous bisphosphonate use has been associated with a rare risk of osteonecrosis of the jaw. Recommendations for management of this condition are discussed.


Stable Self-Assembly of Bovine α-Lactalbumin Exhibits Target-Specific Antiproliferative Activity in Multiple Cancer Cells.
Self-assembly of a protein is a natural phenomenon; however, the process can be performed under a suitable condition in vitro. Since proteins are nontoxic, biodegradable, and biocompatible in nature, they are used in various industrial applications such as biocatalyst, therapeutic agent, and drug carriers. Moreover, their flexible structural state and specific activity are being used as sensors and immensely attract many new applications. However, the inherent potential of protein self-assembly for various applications is yet to be explored in detail. In this study, spherical self-assembly of bovine α-lactalbumin (nsBLA) was synthesized using an optimized ethanol-mediated desolvation process with an average diameter of approximately 300 nm. The self-assembly was found to be highly stable against thermal, pH, and proteases stress. When nsBLA was administered in various cancer cells, it demonstrated high cytotoxicity in three different cancer cells via reactive oxygen species (ROS) generation, whereas it exhibited negligible toxicity in normal human and murine cells. When nsBLA was conjugated with folic acid, it improved the cytotoxicity and perhaps mediated through enhanced cellular uptake in cancer cells through binding with folate receptors. Further, experimental results confirmed that the cancer cell death induced by nsBLA was not caused by apoptosis but a necrotic-like death mechanism. When compared with a well-known protein-based anticancer agent BAMLET (bovine α-lactalbumin made lethal against tumor cell), the self-assembled BLA clearly exhibited higher cytotoxicity to cancer cells than BAMLET. While BAMLET exhibits poor biocompatibility, our nsBLA demonstrated excellent biocompatibility to normal cells. Therefore, in this study, we prepared self-assembled α-lactalbumin that exhibits strong inherent antiproliferative potential in multiple cancer cells which can be used for efficient therapeutic approach in cancer.


Preliminary Investigation on the Relationship between Raman Spectra of Beef and Metmyoglobin and Metmyoglobin Reductase Activity.
A hand-held Raman spectroscopic device was used as a rapid nondestructive testing device to predict the metmyoglobin (MetMb) and metmyoglobin reductase activity (MRA) values on the surface layer of fresh beef. Longissimus dorsi muscles were from 10 young bulls (Holstein-Friesian) from two different cattle farms (group A = 5 and B = 5). The Raman spectra of 100 samples were correlated with the MetMb and MRA values using partial least squares regression (PLSR). Two groups could be discriminated, and the separate correlation models were better than the joint correlation model for the fresh beef. The coefficients of determination are R 2 = 0.81 (group A) and R 2 = 0.87 (group B) for MetMb and R 2 = 0.80 (group A) and R 2 = 0.85 (group B) for MRA. The results show the usefulness of Raman spectra in predicting the inner traits such as MetMb and MRA during meat storage. In conclusion, it is feasible to determine the MetMb and MRA values by Raman spectroscopy. Color is an important indicator of beef freshness and can vary depending on the age, sex, and breed of the cow. They play a very important role in human nutrition. The color of meat is an important indicator of meat freshness, and many researchers are already investigating the causes of color changes. The research was conducted in this environment.


Optimization of a Rolling Triboelectric Nanogenerator Based on the Nano-Micro Structure for Ocean Environmental Monitoring.
The serious environmental pollution and energy crisis have become a global issue, which makes it a pressing task to develop sustainable and clean energy sources. There exists a large amount of renewable energy in the ocean; unfortunately, most resources are underutilized. In this work, we demonstrate a performance-enhancing rolling triboelectric nanogenerator (TENG) based on nano-micro-structured polytetrafluoroethylene (PTFE) films. The nano-micro structure on the PTFE surface can increase the effective contact area and enhance the triboelectric effect, which is beneficial to improve the output performance. As a result, the output voltage and output current are 25.1 V and 7.3 μA, respectively. We further investigate the effect of nano-micro PTFE concentration on the output performance. The TENG based on a 45% concentration of nano-micro PTFE presents the maximum output power. Furthermore, this TENG can effectively harvest water wave energy with various amplitudes and frequencies, which has the potential to harvest ocean energy for environmental monitoring.