[The assembly of low molecular weight neurofilament protein (NF-L) in vitro].
Neurofilaments were isolated from bovine spinal cords by ultra-speed centrifugation and examined by negative staining. The neurofilament triplet proteins: NF-L, NF-M and NF-H were purified by DE-52 anion exchange chromatography in the presence of 6 mol/L urea. The reassembly of NF-L under controlled conditions was studied. NF-L can reassemble into 10 nm width filaments within 60 minutes at physiological condition of around 0.15 mol/L NaCl, 2 mmol/L MgCl2, neutral pH(pH 6.8) and 37 degrees C. In 6 mol/L urea, NF-L was examined as 12 nm-diameter particle by low angle rotary shadowing. When dialyzed against reassembly buffer for 20 minutes, some irregular filaments were formed. Further dialyzed for another 40 minutes, the long smooth filaments appeared. Some filaments were unraveled at the end regions, where existed 2-4 subfilaments. Four subfilaments were more often observed. That is to say, the 10 nm-width filament was composed of 4 subfilaments. While dialyzed against the alkaline buffer containing 0.15 mol/L NaCl, NF-L reconstituted into 45-180 nm-long, 10 nm-width filaments, which were not able to elongate into long filaments.


Phytohormones and their metabolites during long shoot development in Douglas-fir following cone induction by gibberellin injection.
Changes in plant hormones and metabolites in long-shoot stems of interior Douglas-fir (Pseudotsuga menziesii var. glauca (Beissn.) Franco) during cone induction by gibberellic acid (GA) treatment were analyzed by high performance liquid chromatography-electrospray ionization tandem mass spectrometry in multiple reaction monitoring mode. A mixture of GA(4) and GA(7), including small amounts of GA(3) and GA(1), was stem-injected into each tree in amounts of 0, 4, 40 or 400 mg. One week after injection, concentrations of GA(4), GA(7) and GA(3) were elevated in all GA-treated samples. The ratio of GA(4) to GA(7) decreased significantly at Week 3. Absolute concentrations of all gibberellins declined sharply at Week 3 after GA application. After 5 weeks, GA(1) and GA(4) were below detection limits in all samples, and GA(7) and GA(3) were found only in the samples from trees treated with 40 or 400 mg of GA. Endogenous indole-3-acetic acid (IAA) concentrations increased following GA injection, and peaked at Week 2 or Week 3 in the trees treated with 40 or 400 mg GA, respectively. Injection of 400 mg of GA brought about a twofold increase in IAA concentration compared with control values. Injection of 40 and 400 mg of GA caused significant increases in stem dry mass in Week 5. Seed orchard data revealed that injection of either 40 or 400 mg GA enhanced female cone formation, whereas male cone formation was enhanced only by 400 mg GA. Slight decreases in concentrations of abscisic acid (ABA) and isopentenyl adenosine were observed after GA application. No significant changes were detected in the concentrations of ABA metabolites except for a slight decrease in the concentration of 7'-hydroxy ABA. The concentration of ABA declined during the growing season and the concentration of ABA glucose ester increased correspondingly.


Virus-based scaffolds for tissue engineering applications.
One of the major research directions of tissue engineering is to develop artificial scaffolds that can mimic extracellular matrix (ECM) and support the growth of functional cells for the repair of damaged tissues and organs. Recently, virus particles have expanded as nanosized building blocks for materials applications. Viruses represent monodispersed supramolecular assemblies with organized three-dimensional architecture, which can be isolated in high yield and purity with batch-to-batch consistency. In addition, virus particles can be re-engineered by chemical and genetic modification to incorporate multivalent functional ligands with high density and ordered arrangement. In this review, we highlight that the self-assembly of the reengineered viruses can form two-dimensional and three-dimensional scaffolds, which can be employed to support cell growth and regulate cellular functions such as adhesion, spreading and proliferation. In particular, the application of virus-based scaffolds for directed differentiation of pluripotent stem cells for bone and neural regeneration is discussed. Finally, the in vivo behaviors of virus nanoparticles will be discussed for the consideration of tissue engineering applications.


Microdissected bovine X chromosome segment delineates homologous chromosomal regions in sheep and goat.
In this study we microdissected the proximal part band Xq24 of the bovine X chromosome long arm, in which the Xist gene is located in cattle. The obtained DNA fragment was PCR amplified, labelled and used as a probe for cattle, sheep and goat chromosomes. In cattle, as expected, distinct hybridization signals were observed on Xq24. The painting signals were also observed on Xq24 in sheep and goat. The chromosome painting probes can be used for comparative mapping and searching for internal X chromosome rearrangements in Bovidea and may contribute to the understanding of mammalian sex chromosome evolution.


Pharmacokinetic study of the relative bioavailability and bioequivalence after oral intensive or repeated short term treatment with two polyamino acid formulations.
The authors studied the relative bioequivalence and bioavailability of two oral polyamino-acid formulations (packet and flacon), based on 4 amino acids (L-glutamine, L-phosphoserine, L-phosphothreonine and L-arginine) in association with vitamin B12 (Bio-logos, Sigma Tau Pharma S.A). Open-trial testing was carried out after intensive treatment and on the attainment of sustained levels. 50 healthy volunteers (27 males, 23 females), ranging in age from 23 to 32 years, were included in the study. The pharmacokinetic behaviour of the various active ingredients was examined at a haematic level. Possible undesirable side-effects, resulting from treatment, were also examined during the study. The mean pharmacokinetic constants considered (Ke1, Cmax and t1/2) generated an almost overlapping AUC (area under the curves) for all homologous components contained in both pharmaceutical forms. This indicates almost complete bioequivalence. The mean index for the rate of relative bioavailability was, in fact, estimated to be 106.3 +/- 12.4%. Repeated treatment did not appear to disturb the absorption mechanisms of the active ingredients contained in either of the two formulations examined, maintaining the relative bioavailability relationship within a negligible range, with a statistically non-significant difference (Student's t test for coupled data). A few episodes, characterized by slight increases in excitability, were reported for both preparations in two patients (4%).


[Results of a screening project for congenital hypothyroidism in 4 years of experience].
A screening program for congenital hypothyroidism has been starting in Siena since November, 1977 with the Guthrie's test for PKU. According to the recommendations of the Committee of the European Thyroid Association the program were performed on capillary blood samples collected between the fourth and sixth days after birth on an adsorbent paper. The screening began with the measurement of T4 RIA (up to May, 1980), and T4 and TSH RIA (from may, 1980, to december, 1981). At december, 1981, 23.693 newborns have been screened. The recall rate was 2,5% up to may, 1980, and 0,11% from may, 1980 to december, 1981. Ten newborns with congenital hypothyroidism have been detected; the incidence is one in 2.400 live births. There were no cases of transient hypothyroidism and no cases of TBG deficiency. All patients are treated before the age of one month. The diagnosis is confirmed in seven cases at one year of life after stopterapy for one month. Our program confirm the high incidence of congenital hypothyroidism. Clinical control, based on physical and psychomotor development testing in seven patients treated confirmed that all infants are normal.


Role of metabolism and oxidation-reduction cycling in the cytotoxicity of antitumor quinoneimines and quinonediimines.
Quinone(di)imines are nitrogen analogues of quinones in which one or both quinone oxygens are replaced by an imino group. A series of quinone(di)imines with antitumor activity has been studied for its in vitro chemical reactivity, metabolism, acute toxicity to primary cultured rat hepatocytes, and growth-inhibitory activity with Chinese hamster ovary (CHO) cells. The quinone(di)imines exhibited a wide range of activity as substrates for metabolism by hepatic microsomal flavoenzymes. The maximum rate of quinone(di)imine metabolism was more than 7.5-fold greater than reported for metabolism of quinones. Some quinone(di)imines formed free radicals that could be detected by electron spin resonance spectroscopy. 2-Amino-1,4-naphthoquinoneimine gave a short-lived electron spin resonance signal that could be detected only under aerobic conditions. 2,3',6-Trichloroindophenol gave an electron spin resonance signal in air that was stable for 24 h. Most quinone(di)imines underwent oxidation-reduction cycling to form the superoxide anion radical, but some quinone(di)imines, although rapidly metabolized, formed little or no superoxide anion radical. Quinone(di)imines were relatively toxic to hepatocytes and CHO cells, and some quinone(di)imines were more toxic to one cell type than the other. The log 1-octanol/water partition coefficient showed an optimal value of 2.61 for toxicity against both cell types. In hepatocytes the more toxic quinone(di)imines were the most rapidly metabolized. For a subgroup of quinone(di)imines toxicity to hepatocytes and CHO cells appeared to be related to the ability to form a semiquinone(di)imine free radical. Toxicity of quinone(di)imines to hepatocytes and CHO cells was not related to superoxide anion radical formation, and toxicity to CHO cells was not affected by exclusion of oxygen during exposure of the cells to the compounds. The rate of chemical addition of quinone(di)imines to reduced glutathione did not correlate with toxicity. An understanding of the mechanisms of acute toxicity and growth-inhibitory activity of quinone(di)imines could lead to the design of more selective quinonoid antitumor agents.


Antibiotic-resistant staphylococci in a teaching hospital.
A large, continuing outbreak of infection and colonisation with a Staphylococcus aureus which is resistant to methicillin and gentamicin is reported. Affected patients and staff members seen between September, 1980, and August, 1981, are reviewed in detail. Methods of management of such persons and their treatment, if required, are discussed. The antibiotic-resistant Staph. aureus is readily disseminated in hospitals and may cause outbreaks of infection in wards, which require isolation of affected patients in the attempt to control the problem. It is suggested that a special isolation unit is needed. Use of the few effective antibiotic agents should be restricted. Despite these measures, the spread of this organism may not be contained.


Different electrophysiological profiles and treatment response in 'typical' and 'atypical' chronic inflammatory demyelinating polyneuropathy.
Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into 'typical' CIDP and 'atypical' subtypes such as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). To assess the frequency of CIDP subtypes, and to elucidate clinical and electrophysiological features, and treatment response in each subtype. We reviewed data from 100 consecutive patients fulfilling criteria for CIDP proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. The Kaplan-Meier curve was used to estimate long-term outcome. Patients were classified as having typical CIDP (60%), MADSAM (34%), demyelinating acquired distal symmetric neuropathy (8%) or pure sensory CIDP (1%). Compared with patients with MADSAM, patients with typical CIDP showed more rapid progression and severe disability, and demyelination predominant in the distal nerve segments. MADSAM was characterised by multifocal demyelination in the nerve trunks. Abnormal median-normal sural sensory responses were more frequently found for typical CIDP (53% vs 13%). Patients with typical CIDP invariably responded to corticosteroids, immunoglobulin or plasmapheresis, whereas patients with MADSAM were more refractory to these treatments. The Kaplan-Meier analyses showed that 64% of patients with typical CIDP and 41% of patients with MADSAM had a clinical remission 5 years later (p=0.02). Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. In typical CIDP, the distal nerve terminals and possibly the nerve roots, where the blood-nerve barrier is anatomically deficient, are preferentially affected, raising the possibility of antibody-mediated demyelination, whereas cellular immunity with breakdown of the barrier may be important in MADSAM neuropathy.


Transcription analysis of the Bacillus subtilis PucR regulon and identification of a cis-acting sequence required for PucR-regulated expression of genes involved in purine catabolism.
The PucR protein of Bacillus subtilis has previously been suggested to regulate the expression of 15 genes, pucABCDE, pucFG, pucH, pucI, pucJKLM, pucR, and gde, all of which encode proteins involved in purine catabolism. When cells are grown under nitrogen-limiting conditions, the expression of these genes is induced and intermediary compounds of the purine catabolic pathway affect this expression. By using pucR deletion mutants, we have found that PucR induces the expression of pucFG, pucH, pucI, pucJKLM, and gde while it represses the expression of pucR and pucABCDE. Deletions in the promoters of the five induced operons and genes combined with bioinformatic analysis suggested a conserved upstream activating sequence, 5'-WWWCNTTGGTTAA-3', now named the PucR box. Potential PucR boxes overlapping the -35 and -10 regions of the pucABCDE promoter and located downstream of the pucR transcription start point were also found. The positions of these PucR boxes are consistent with PucR acting as a negative regulator of pucABCDE and pucR expression. Site-directed mutations in the PucR box upstream of pucH and pucI identified positions that are essential for the induction of pucH and pucI expression, respectively. Mutants with decreased pucH or increased pucR expression obtained from a library of clones containing random mutations in the pucH-to-pucR intercistronic region all contained mutations in or near the PucR box. The induction of pucR expression under nitrogen-limiting conditions was found to be mediated by the global nitrogen-regulatory protein TnrA. In other gram-positive bacteria, we have found open reading frames that encode proteins similar to PucR located next to other open reading frames encoding proteins with similarity to purine catabolic enzymes. Hence, the PucR homologues are likely to exert the same function in other gram-positive bacteria as PucR does in B. subtilis.


No evidence for homeoviscous adaptation in intertidal snails: analysis of membrane fluidity during thermal acclimation, thermal acclimatization, and across thermal microhabitats.
Many eurythermal organisms alter composition of their membranes to counter perturbing effects of environmental temperature variation on membrane fluidity, a process known as homeoviscous adaptation. Marine intertidal gastropods experience uniquely large thermal excursions that challenge the functional integrity of their membranes on tidal and seasonal timescales. This study measured and compared membrane fluidity in marine intertidal snail species under three scenarios: (1) laboratory thermal acclimation, (2) thermal acclimatization during a hot midday low tide, and (3) thermal acclimatization across the vertical intertidal zone gradient in temperature. For each scenario, we used fluorescence polarization of the membrane probe DPH to measure membrane fluidity in individual samples of gill and mantle tissue. A four-week thermal acclimation of Tegula funebralis to 5, 15, and 25°C did not induce differences in membrane fluidity. Littorina keenae sampled from two thermal microhabitats at the beginning and end of a hot midday low tide exhibited no significant differences in membrane fluidity, either as a function of time of day or as a function of thermal microhabitat, despite changes in body temperature up to 24°C within 8 h. Membrane fluidities of a diverse group of snails collected from high, middle, and low vertical regions of the intertidal zone varied among species but did not correlate with thermal microhabitat. Our data suggest intertidal gastropod snails do not exhibit homeoviscous adaptation of gill and mantle membranes. We discuss possible alternatives for how these organisms counter thermal excursions characteristic of the marine intertidal zone.


Development of an instrument to measure professional attitudes in nursing students in Turkey.
The aim of the current study was to develop an instrument to determine the professional attitude of nursing students. The data were collected through a scale developed by the authors with the statements on attitude, including 8 sub-groups and 28 items. This was a Likert-type scale, ranging from 5 to 1. The sampling of the investigation comprised 1339 final-year undergraduate nursing students in Turkey. Eight factors were defined depending on the reliability and validity study of the professionalism instrument for nursing students. These factors accounted for 65.5% of the total variance. The correlation of the sub-factors in the scale ranged from 0.71 to 0.84. Cronbach alpha value was 0.90 and Cronbach alpha coefficient for sub-factors was between 0.71 and 0.84. Item test correlations calculated for the validity and the homogeneity of the instrument's items were between 0.30 and 0.63. In conclusion, it was found that the instrument was a valid and reliable assessment tool that can be used to measure professional attitudes of nursing students.


Comparison of mortality rates and functional results after transtibial and transfemoral amputations due to diabetes in elderly patients-a retrospective study.
This study aimed to compare mortality rates and functional results of transtibial and transfemoral amputations in elderly patients with diabetes. 87 amputees [54 (62.1%) transtibial and 33 (37.9%) transfemoral] were included. Mean ages were 70.7 and 69.3 years in transfemoral and transtibial groups, respectively. Mean follow up time was 41.8 months. Amputee Mobility Predictor scores (with and without prosthesis) and Barthel Daily Living Index were used for functional evaluation of the survivors. First year mortality rates were 29.6% and 30.3% in transtibial and transfemoral groups, respectively. Overall mortality rate of both groups was 65.5% (66.7% in transtibial and 63.6% in transfemoral group). There was no difference between mortality rates of two groups. Duration between surgery and death was significantly shorter in transfemoral group. The mean Amputee Mobility Predictor scores (with prosthesis) of the transtibial and transfemoral groups were 32.3 and 26.9 points, respectively. The average Amputee Mobility Predictor scores (without prosthesis) of the transtibial and transfemoral groups were 29.5 and 22.7 points respectively. The differences between two groups' scores were significant. The mean Barthel Daily Living Index scores of the transtibial and transfemoral groups were 82.5 and 80.2 points respectively. The difference was not significant. High mortality rates and morbidities after major lower limb amputations emphasize the importance of preventive measures and foot care in patients with diabetes.


[100 years of skin hospital Giessen: from the lupus hospice to the center of dermatology and andrology].
For one hundred years the skin hospital at the clinical center of Giessen University has been an important institution for patients with skin diseases. The hospital has not only been an address for patients to turn to but also a place of work and training for health personnel. Its profile has been especially established, formed and developed by the chairs of dermatology. Its development was strongly influenced by the treatment of lupus and STDs (sexually transmitted diseases). This is exemplary for the development of other German dermatology clinics.


DTPA complexation of bismuth in human blood serum.
The in vivo(212)Pb/(212)Bi generator is promising for application in targeted alpha therapy (TAT) of cancer. One main limitation of its therapeutic application is due to potential release of (212)Bi from the radioconjugate upon radioactive decay of the mother nuclide (212)Pb, potentially leading to irradiation of healthy tissue. The objective of the present work is to assess whether the chelate CHX-A''-DTPA (N-(2-aminoethyl)-trans-1,2-diaminocyclohexane-N,N',N''-pentaacetic acid) bound to a biological carrier molecule may be able to re-complex released (212)Bi under in vivo conditions to limit its translocation from the target site. CHX-A''-DTPA was bound to bovine gamma globulin (BGG) to mimic a model conjugate and the stability of the Bi-CHX-A''-DTPA-BGG conjugate was studied in blood serum by ultrafiltration. TRLFS experiments using Cm(III) as a fluorescent probe demonstrated that linking CHX-A''-DTPA to BGG does not affect the coordination properties of the ligand. Furthermore, comparable stability constants were observed between Bi(III) and free CHX-A''-DTPA, BGG-bound CHX-A''-DTPA and DTPA. The complexation constants determined between Bi(III) and the chelate molecules are sufficiently high to allow ultra trace amounts of the ligand to efficiently compete with serum transferrin controlling Bi(III) speciation in blood plasma conditions. Nevertheless, CHX-A''-DTPA is not able to complex Bi(III) generated in blood serum because of the strong competition between Bi(III) and Fe(II) for the ligand. In other words, CHX-A''-DTPA is not "selective" enough to limit Bi(iii) release in the body when applying the (212)Pb/(212)Bi in vivo generator.


Safety and efficacy of levetiracetam for the treatment of partial onset seizures in children from one month of age.
Epilepsy is a common neurological disorder in the pediatric population, affecting up to one percent of children, and for which the mainstay of treatment is anticonvulsant medication. Despite the frequent use of anticonvulsant drugs, remarkably little is known about the safety and efficacy of most of these medications in the pediatric epilepsy population. Of 34 anticonvulsants currently approved for use by the US Food and Drug Administration (FDA), only 13 have been approved for use in children. Although infants and young children are disproportionately affected by epilepsy, there are currently only three anticonvulsant medications that have been specifically evaluated and approved for use in children younger than 2 years of age. In 2012, the FDA approved levetiracetam as an adjunctive treatment for partial onset seizures in infants and children from one month of age. Here we review the available data on levetiracetam in the pediatric epilepsy population. We first discuss the pharmacological profile of levetiracetam, including its mechanism of action, formulations and dosing, and pharmacokinetics in children. We then review the available efficacy, safety, and tolerability data in children from one month of age with partial onset seizures. We conclude that the current data leading to the approval of levetiracetam for use in infants and children with partial onset seizures is encouraging, although more work needs to be done before definitive conclusions can be drawn about the efficacy of levetiracetam across different pediatric age groups.


A multi-enzyme electrophoretic system for the identification of seminal fluid from postmortem specimens.
The screening of autopsy specimens, vaginal, buccal, and rectal swabs, for the presence of seminal fluid in rape homicide investigations utilizing classical techniques can lead to erroneous results. In the absence of spermatozoa, techniques are needed which can help to identify seminal fluid. This report illustrates the use of a multi-enzyme electrophoretic approach identifying seminal acid phosphatase (SAP) and lactic acid dehydrogenase (LDH-X) as an initial screening procedure. Subsequent analyses for the presence of acid and alkaline phosphatase (semiquantitative) yield information which can help identify false-positive SAP's. Additionally, salivary amylase can be tentatively identified using the same multi-enzyme procedure which informs the investigator of possible salivary contamination of the sample and possible erroneous PGM results. Statistics utilizing the multi-enzyme approach in case work are also presented.


Systemic therapy in the management of metastatic or advanced salivary gland cancers.
Salivary gland cancers are very rare tumors. They are characterized by a histologic heterogeneity and a poor outcome. According to this rarity, few prospective data are available to date. No standard recommendations could be held for the use of systemic therapy in these tumors. Several case reports and small studies have investigated the contribution of different agents of chemotherapy. With the extension of molecular biology approach in oncology several signaling pathways have been discovered in different cancers including salivary gland cancers; thus a number of targeted therapies have been investigated. This paper reviewed exhaustively the studies investigating the role of systemic therapies (chemotherapy, targeted therapy, hormone therapy) in salivary gland cancers.


Cytotoxic activity of a podophyllotoxin-like lignan from Linum tauricum Willd.
The present study describes the preliminary evaluation of the cytotoxic activity of a podophyllotoxin-like compound 4'-demethyl-6-methoxypodophyllotoxin (4'-DM-6-Mptox), isolated as one of the main lignans of Linum tauricum Willd. ssp. tauricum. The cytotoxic effects 4'-DM-6-Mptox were assessed by the MTT-dye reduction assay against the human leukemic cell lines HL-60, BV-173 and LAMA-84. DNA-fragmentation analysis and NF-kB inhibition assay were performed in order to elucidate some of the mechanistic aspects of the cytotoxic action of the investigated compound. 4'-DM-6-Mptox was found to exert prominent cytotoxicity, with IC50 values being several-fold lower than those of the referent antineoplastic agent etoposide. The DNA-fragmentation analysis revealed that 4'-DM-6-Mptox treatment triggered apoptosis in BV-173 and HL-60 cells. In our hands 4'-DM-6-Mptox was found to induce concentration-dependent NF-kB inhibition in HeLa cells as assessed by the IL-6 luciferase gene reporter assay, which though not quite prominent, at least partly contributes to the cytotoxic potential of the tested lignan. On the basis of the results obtained it could be concluded that 4'-DM-6-Mptox necessitates further pharmacological and toxicological evaluation as a possible chemotherapeutic agent. Furthermore due to its relatively high concentrations in the described plant source the possibility for its use as a precursor for the semisynthetic production of lignan-based drugs, could be considered.


Combination of FLG mutations and SNP of TSLP (rs1898671) influence on atopic dermatitis occurrence.
Atopic dermatitis (AD) is a common, chronic, relapsing and heterogeneous inflammatory skin disease. Its main causes are genetic predispositions, the epidermal barrier defect, and immune system dysfunction. Thymic stromal lymphopoietin (TSLP) is highly expressed in the epidermis of AD patients and its production is triggered by exposure to environmental factors, allergens, microorganisms and irritants. To search for the associations between rs1898671 polymorphism in the promotor region of the TSLP gene (SNP) and AD occurrence and course. The frequency of polymorphism occurrence was examined, connection with IgE level, the severity of AD, itching, and concomitant asthma occurrence and combination with FLG gene mutations (2282del4, R501X) in the population of northern Poland. Blood samples were collected from 239 patients with AD and 170 controls. SNP of TSLP and FLG null mutations were analysed. PCR and RFLP restriction fragment length polymorphism analysis was used. No polymorphisms of studied cytokines caused more frequent occurrence of AD compared to controls. We found no associations between TSLP gene polymorphism and AD severity (p = 0.395), IgE level (p = 0.895), VAS (p = 0.918) or concomitant asthma (p = 0.742). The SNP of TSLP rs1898671 does not influence the AD course and occurrence. 2282del4 FLG mutation is a key influencer in AD. However, the coexistence of FLG mutations and SNP of TSLP may play a protective role.


Correction: Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine.
Correction for 'Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine' by Judith M. Curran et al., Lab Chip, 2010, 10, 1662-1670.


Support for present and future leaders.
Sam Foster, Chief Nurse, Oxford University Hospitals, considers how clinical leaders in the NHS can best be empowered to lead, in light of the recent Kerr report.


Precise measurement of the CP violation parameter sin2φ1 in B0→(cc¯)K0 decays.
We present a precise measurement of the CP violation parameter sin2φ1 and the direct CP violation parameter A(f) using the final data sample of 772×10(6) BB[over ¯] pairs collected at the Υ(4S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. One neutral B meson is reconstructed in a J/ψK(S)(0), ψ(2S)K(S)(0), χ(c1)K(S)(0), or J/ψK(L)(0) CP eigenstate and its flavor is identified from the decay products of the accompanying B meson. From the distribution of proper-time intervals between the two B decays, we obtain the following CP violation parameters: sin2φ1=0.667±0.023(stat)±0.012(syst) and A(f)=0.006±0.016(stat)±0.012(syst).


Manganese(iii) acetate catalyzed oxidative amination of benzylic C(sp3)-H bonds with nitriles.
Mn-Catalyzed oxidative amination of benzylic C(sp3)-H bonds with nitriles is disclosed, which enables the synthesis of a broad range of secondary amides in moderate to excellent yields under mild conditions. The interaction between Mn(iii) and DDQ facilitates the oxidation and makes it highly efficient and selective.


Crystal structure of Junin virus nucleoprotein.
Junin virus (JUNV) has been identified as the aetiological agent of Argentine haemorrhagic fever (AHF), which is a serious public health problem with approximately 5 million people at risk. It is treated as a potential bioterrorism agent because of its rapid transmission by aerosols. JUNV is a negative-sense ssRNA virus that belongs to the genus Arenavirus within the family Arenaviridae, and its genomic RNA contains two segments encoding four proteins. Among these, the nucleoprotein (NP) has essential roles in viral RNA synthesis and immune suppression, but the molecular mechanisms of its actions are only partially understood. Here, we determined a 2.2 Å crystal structure of the C-terminal domain of JUNV NP. This structure showed high similarity to the Lassa fever virus (LASV) NP C-terminal domain. However, both the structure and function of JUNV NP showed differences compared with LASV NP. This study extends our structural insight into the negative-sense ssRNA virus NPs.


Detection of proteins in human amniotic fluid using two-dimensional gel electrophoresis.
Samples of human amniotic fluid from 48 pregnancies were examined by high resolution two-dimensional gel electrophoresis and the positions of the major peptides were mapped. Many of the proteins in amniotic fluid also occur in adult and fetal serum. Three regions in the amniotic fluid maps could be defined containing peptides which were not found in adult or fetal serum. The concentration of these peptides is variable and their origin is as yet unknown. Many differences were seen between adult and fetal serum proteins.


The Relationship between Body Fat Percent and Bone Mineral Density in Korean Adolescents: The Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1), 2010.
The relationships of total and regional body fat percent with bone mineral density (BMD) in Korean adolescents were examined using the Fifth Korea National Health and Nutrition Examination Survey (KNHANES V-1), 2010. Body fat percent at whole body (WBFP), trunk (TBFP), and extremities (both upper and lower extremities fat mass/body weight, EBFP), ratio of trunk fat mass to extremities fat mass (TEFR), and BMD at whole body, total femur, and lumbar spine were measured by dual energy X-ray absorptiometry in a population-based sample of 433 boys and 362 girls, aged 12 to 18 years. The analyses were conducted using linear regression analysis with complex sampling design. After adjusting for confounders such as age, height, weight, serum 25-(OH) vitamin D concentration, energy intake, calcium intake, physical activity, and menarche status for girls, WBFP, TBFP, and EBFP were inversely associated with whole and regional BMD in both sexes (P < 0.05). TEFR was positively associated with whole and regional BMD in boys after adjusting for confounders, while it was negatively associated in girls (P < 0.05). However, the associations were non-significant when bone mass-free lean mass was adjusted instead of bodyweight except for a positive association between TEFR and BMD in boys. In Korean adolescents, total and regional body fat percent is not independently associated with BMD after adjusting for bone mass-free lean mass but higher fat in trunk as compared to extremities may be protective for BMD in boys.


Retrovirus-like particles released by human prostatic cells.
A cell strain has been obtained from an explant culture of a human prostatic tissue. The tissue was diagnosed as benign prostatic hyperplasia. Cultured cells displayed human male karyotype and chromosome model number of 43--46. Cultures of these cells appear to release retrovirus-like entities. The extracellular particulate material obtained from the culture medium showed the following characteristics: (1) it banded at a density of 1.12--1.18 g/ml in a sucrose density gradient; (2) it contained particles with a sedimentation rate approximating that of the known retroviruses; (3) these particles contained RNA and RNA-directed DNA polymerase; (4) the RNA-directed DNA polymerase utilized poly (Cm) as a template, and (5) the particles synthesized DNA in an endogenous DNA polymerase reaction. The DNA thus synthesized was associated with RNA, some of it with high molecular weight RNA. These observations can be interpreted to suggest that human prostatic cells produce retrovirus(es). However, we were not able to detect a 60--70S RNA species in the labeled RNA of the released particles. The isolated RNA, however, displayed a 30--35S component.


High prevalence of latent tuberculosis and bloodborne virus infection in a homeless population.
Urban homeless populations in the UK have been shown to have high rates of active tuberculosis, but less is known about the prevalence of latent tuberculosis infection (LTBI). This study aimed to estimate the prevalence of LTBI among individuals using homeless hostels in London. We performed a cross-sectional survey with outcome follow-up in homeless hostels in London. Our primary outcome was prevalence of LTBI. Recruitment for the study took place between May 2011 and June 2013. To estimate an LTBI prevalence of 10% with 95% CIs between 8% and 13%, we required 500 participants. 491/804 (61.1%) individuals agreed to be screened. The prevalence of LTBI was 16.5% (81/491; 95% CI 13.2 to 19.8). In UK-born individuals, a history of incarceration was associated with increased risk of LTBI (OR 3.49; 95% CI 1.10 to 11.04; P=0.018) after adjusting for age, length of time spent homeless and illicit drug use. Of the three subjects who met English treatment guidelines for LTBI at the time of the study, none engaged with services after referral for treatment. Prevalence of past hepatitis B infection was 10.4% (51/489; 95% CI 7.7 to 13.1), and 59.5% (291/489; 95% CI 55.1 to 63.9) of individuals were non-immune. Prevalence of current hepatitis C infection was 10.4% (51/489; 95% CI 7.8 to 13.1). This study demonstrates the high prevalence of LTBI in homeless people in London and the associated poor engagement with care. There is a large unmet need for LTBI and hepatitis C infection treatment, and hepatitis B vaccination, in this group.


Multicompartment, numerical model of cellular events in the pharmacokinetics of gene therapies.
DNA expression vectors may be administered to patients like conventional medicines to have a finite and controlled duration of action. The clinical application of these medicines will require a precise understanding of the kinetics of the administered gene, the mRNA transcript, and the gene product. The apparent kinetic properties of the therapeutic gene product, including the level and duration of action, will be determined by various intrinsic kinetic processes including: (i) distribution and biological fate of the DNA expression vector; (ii) rates of DNA uptake into cells and dynamics of intracellular trafficking; (iii) half-life of the DNA vector in the cell; (iv) transcription rate; (v) half-life of mRNA; (vi) translation rate; and (vii) post-translational processing, distribution, and fate of the gene product. To consider in a theoretical manner how the intrinsic kinetics of cellular processes may affect the apparent level of a therapeutic gene product over time, we have constructed a multicompartment, numerical model. The model has six compartments, designated MILIEU, ENDOSOME, CELL, RNA, PROTEIN, and PRODUCT. The apparent level and kinetics of the gene product over time are calculated with different values for the intrinsic t1/2 of DNA in the MILIEU, ENDOSOME, and CELL; the intrinsic t1/2 of mRNA; the intrinsic t1/2 of the gene product; endosomal stability; and transcription rate. The model demonstrates how first-order kinetics can result from the summation of complex kinetic processes and provides a theoretical basis for future pharmacokinetic studies. This theoretical model illustrates how the half-lives of DNA, RNA, and gene product each affect the level of the product and highlights strategies for enhancing the therapeutic profile of gene therapies.


Prospective analysis of 16S rDNA as a highly sensitive marker for bacterial presence in Peyronie's disease plaques.
Previous studies have implicated an infectious agent induced pathogenesis in Peyronie's disease. To our knowledge an association with venereal diseases or other infectious diseases has not been demonstrated to date, although Peyronie's disease is an inflammatory disorder. In case of an infectious origin of the disorder bacteria or at least their fragments should occur in the plaque. We investigated prospectively the occurrence of 16S rDNA as a highly sensitive marker for the presence of bacteria in inflammatory processes. In 19 patients with idiopathic Peyronie's disease biopsy of the tunica albuginea was sampled. A total of 16 men with no evidence of Peyronie's disease served as the control group. In these men tissue from the tunica albuginea was obtained during penile prosthesis implantation for erectile dysfunction or during a Nesbit procedure for congenital penile curvature. Screening for bacterial DNA was performed prospectively using a polymerase chain reaction targeting bacterial 16S rDNA. In the tunica albuginea specimen 16S rDNA was not detectable in patients with Peyronie's disease or in the control group. The results of this study do not indicate an association between Peyronie's disease and bacterial infection.


[Drug sensitivity test against malignant gliomas].
In treating brain tumors with chemotherapy, the choice of drug is most important since human tumors have different drug sensitivities and growth rates. We have been studying the therapeutic effect of anticancer drugs against malignant brain tumors in the following in vivo models. 1) Human glioma-bearing nude mice. 2) Methylcholantrene-induced 203Gl mouse glioma-bearing immunocompetent C57BL/6 mice. 3) Human gliomas transplanted into the chorioallantoic membrane of chick embryos. We evaluated the advantages of each model for anti-cancer drug sensitivity tests. 1) Human glioma-bearing nude mice were found to be most useful in predicting the direct effects of anticancer drugs. We evaluated the effects of several drugs such as ACNU or interferons in six glioma strains transplanted into nude mice. 2) Immunocompetent C57BL/6 mice models were found useful in predicting the therapeutic effects of biological response modifiers. In this model, we can also evaluate changes in immunological parameters such as NK activities or T cell subsets. 3) In the drug sensitivity test using the CAM of chick embryos, various kinds of gliomas could be grafted with a high rate of success. The tumor reduction rate of the sensitivity test using this system tended to agree with that using nude mice. This test was found to be useful in predicting the effect of drugs against gliomas directly resected from individual patients.


The Effect of Bonding Strategy and Aging on Adhesion to Primary Enamel: An In-Vitro Study.
Resin composites are commonly used in pediatric dentistry, but there is limited evidence on adhesion to primary teeth, especially primary enamel. In this study, three bonding strategies were assessed - one-step self-etch (1-SE), two-step self-etch (2-SE), and three-step etch-and-rinse (3-ER) - by measuring the immediate and aged microshear bond strength (µSBS) to sound primary enamel. 120 extracted human primary molars with sound buccal surfaces were used for µSBS testing. Six adhesive protocols (two per bonding strategy) were selected and µSBS was measured either after 24 h or 10,000 thermal cycles (n = 10). Confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM) were used to determine failure modes. Furthermore, 18 primary molars were etched using the different adhesive protocols (n = 3) for the measurement of surface roughness (Sa) using CLSM and morphological analysis using SEM. After 24 h, there was no significant difference in µSBS between 1-SE and 2-SE strategies (p = 0.96), but the 2-SE strategy yielded significantly higher µSBS after thermocycling (p < 0.001). The highest µSBS was obtained using the 3-ER strategy regardless of aging (p < 0.001). The 3-ER strategy clearly exposed enamel prisms and resulted in the highest Sa (p < 0.001). In contrast, if SE strategies were used, enamel prisms were barely recognizable, and Sa was not significantly different from baseline (p > 0.95). The 3-ER strategy is optimal for bonding to primary enamel. The etching effect of SE strategies is weaker, resulting in lower µSBS. Thermocycling revealed that the bonding durability of the 1-SE strategy is inferior to that of to multi-step strategies.


Quantifying uranium complexation by groundwater dissolved organic carbon using asymmetrical flow field-flow fractionation.
The long-term mobility of actinides in groundwaters is important for siting nuclear waste facilities and managing waste-rock piles at uranium mines. Dissolved organic carbon (DOC) may influence the mobility of uranium, but few field-based studies have been undertaken to examine this in typical groundwaters. In addition, few techniques are available to isolate DOC and directly quantify the metals complexed to it. Determination of U-organic matter association constants from analysis of field-collected samples compliments laboratory measurements, and these constants are needed for accurate transport calculations. The partitioning of U to DOC in a clay-rich aquitard was investigated in 10 groundwater samples collected between 2 and 30 m depths at one test site. A positive correlation was observed between the DOC (4-132 mg/L) and U concentrations (20-603 microg/L). The association of U and DOC was examined directly using on-line coupling of Asymmetrical Flow Field-Flow Fractionation (AsFlFFF) with UV absorbance (UVA) and inductively coupled plasma-mass spectrometer (ICP-MS) detectors. This method has the advantages of utilizing very small sample volumes (20-50 microL) as well as giving molecular weight information on U-organic matter complexes. AsFlFFF-UVA results showed that 47-98% of the DOC (4-136 mg C/L) was recovered in the AsFlFFF analysis, of which 25-64% occurred in the resolvable peak. This peak corresponded to a weight-average molecular weight of about 900-1400 Daltons (Da). In all cases, AsFlFFF-ICP-MS suggested that<or=2% of the U, likely present as U(VI), was complexed with the DOC. This result was in good agreement with the U speciation modeling performed on the sample taken from the 2.3 m depth, which predicted approximately 3% DOC-complexed U. This good agreement suggests that the AsFlFFF-ICP-MS method may be very useful for determining U-organic matter association in small volume samples. Because the pH (7.0-8.1) and carbonate concentrations of these waters are typical of many groundwaters, these data suggested that facilitated transport of U by DOC may be limited in its importance in many groundwater systems.


Combined Plate and Long Screw Fixation of Transverse Condylar Head Fractures.
We describe a method of fixing transverse condylar head fractures using a combination of a plate and long screw fixation. In the technical procedure, a 4-hole mini-plate was placed on the lateral side of the condylar head and the condylar stump after the fracture reduction. The first hole was drilled in the lateral side of the condylar head, and one 9 mm mini-screw was inserted, a second hole drilled from the lateral side of the condyle stump through the medial pole of the condylar head and a 16 mm screw was inserted in an oblique direction from inferior to superior, then 2 more 9 mm mini-screws were inserted just below the long one to complete the procedure. This technique showed excellent results in both short and long-term stability of and healing of the fracture. Furthermore, it is more standardized, reproducible, and less technically demanding.


Adult campfire burns: two avenues for prevention.
Campfires are a common component of outdoor festivities. Pediatric campfire burns have been well described. Adult campfire injuries also are common and have several important distinguishing characteristics. We performed a retrospective review of adult patients admitted with campfire burns to our burn center from July 1998 to July 2003. Medical records were reviewed with attention to mechanism of injury, intoxication level, burn size, and surgeries performed. A total of 27 patients with this injury were treated as inpatients over the course of the study period. Two distinct mechanisms of injury emerged: 1) contact with the campfire and 2) flash/flame injuries from igniting the fire. Eighty-one percent (13/16) of patients who sustained contact burns were intoxicated, as compared with 11% (1/11) of those who sustained flash/flame injuries. Nearly half of the patients with contact burns and more than half the patients with flash/flame burns required excision and grafting.


Unsupported valvuloplasty for degenerative mitral regurgitation: long-term results.
The advantages of valve repair for treatment of degenerative mitral regurgitation are well established. The procedure is associated with low mortality and morbidity rates, and low indices of reoperation, thromboembolic events and endocarditis have been reported. In most series, annuloplasty rings are implanted, but some institutions give preference to unsupported valvuloplasty. To assess the clinical outcome of patients submitted to unsupported valvuloplasty for degenerative mitral regurgitation. Between January 1980 and January 2003, 116 patients were submitted to the procedure. A total of 62 (53.4%) were men, and mean age was 47.2 +/- 16.5 years. The procedures included: Wooler annuloplasty (65.5%), unilateral annuloplasty (15.5%), quadrangular resection of the posterior leaflet (35.3%), anterior chordal shortening (20.7%), posterior chordal shortening (6.9%), and calcium debridement (0.9%). Mean follow-up was 6.5 +/- 5.1 years, and the longest follow-up was 24 years. Mortality was 0.86% (1 pt) early and 6.03% (7 pt) late. Actuarial survival was 85.3% in 20 years. Most patients (55.2%) presented preoperative NYHA functional class III, whereas class I was more frequent in the postoperative period (66.4%). Thromboembolic complications were observed in 4 patients (3.4%), and no correlation was seen with atrial fibrillation. Freedom from thromboembolic events was 94.8%, and similar results were observed for bacterial endocarditis. Survival free from reoperation was 79%, and 53% at 5 and 10 years, respectively. Unsupported valvuloplasty is effective and safe for treatment of degenerative mitral regurgitation, representing an adequate therapeutic alternative for selected cases.


Lead exposure study among workers in lead acid battery repair units of transport service enterprises, Addis Ababa, Ethiopia: a cross-sectional study.
Lead exposure is common in automobile battery manufacture and repair, radiator repair, secondary smelters and welding units. Urinary Aminolevulinic acid has validity as a surrogate measure of blood lead level among workers occupationally exposed to lead. This study had therefore assessed the magnitude of lead exposure in battery repair workers of three transport service enterprises. To this effect, a cross-sectional study was carried out on lead exposure among storage battery repair workers between November 2004 and May 2005 from Anbasa, Comet and Walia transport service enterprises, Addis Ababa, Ethiopia. Subjective information from the workers was obtained by making use of structured questionnaire. Other information was obtained from walkthrough evaluation of the repair units. Aminolevulinic acid levels in urine were used as an index of the exposure. This was coupled to measurements of other relevant parameters in blood and urine collected from adult subjects working in the repair units as well as age matched control subjects that were not occupationally exposed to lead. Aminolevulinic acid was determined by spectrophotometry, while creatinine clearance, serum creatinine, urea and uric acid levels were determined using AMS Autolab analyzer. Urinary aminolevulinic acid levels were found to be significantly higher in exposed group (16 mug/ml +/- 2.0) compared to the non-exposed ones (7 mug/ml +/- 1.0) (p < 0.001). Alcohol taking exposed subjects exhibited a significant increase in urinary aminolevulinic acid levels than non-alcohol taking ones (p < 0.05). Moreover, urinary aminolevulinic acid levels of exposed subjects increased with age (p < 0.001) as well as duration of employment (p < 0.001). Whereas serum uric acid levels of exposed subjects was significantly higher than non-exposed ones (p < 0.05), no statistically significant difference had been found in renal indices and other measured parameters between exposed and non-exposed subjects. From the questionnaire responses and walkthrough observations, it was also known that all the repair units did not implement effective preventive and control measures for workplace lead exposure. Taken together, these findings indicated that workers in lead acid battery repair units of the transport service enterprises are not protected from possibly high lead exposure. Thus, strict enforcement of appropriate and cost effective preventive and control measures is required by all the enterprises.


Primary ovarian pregnancy.
Primary ovarian pregnancy is a relatively rare form of ectopic pregnancy with an incidence of 1/6000 - 1/40000 pregnancies. A 25-year-old woman, gravida 1, parity 0, presented with vaginal bleeding after 8 weeks of amenorrhea. Pelvic examination revealed a left adnexal mass and transvaginal ultrasound confirmed a left adnexal echocomplex mass with free fluid in the cul-de-sac. Serum beta hCG was 3441 mIU/mL. Emergency exploratory laparotomy was performed with a preoperative diagnosis of left ectopic pregnancy, suspected of ovarian pregnancy. Ruptured left ovarian pregnancy was intraoperatively diagnosed. Left salpingo-oophorectomy was performed. The histopathology confirmed ovarian pregnancy. She was well at discharge and throughout a 4-week period of follow-up. Although primary ovarian pregnancy is rare and difficult to diagnose clinically and even intraoperatively, it can be detected early with the use of combined transvaginal ultrasonography and serum beta hCG The standard of care is conservative treatment in order to preserve the patient's fertility.


Activated mast cells in periprosthetic joint infection-associated tissue.
Periprosthetic joint infection (PJI) is a devastating complication of total joint arthroplasty surgery. Increased densities of activated mast cells have been predicted to be present in PJI compared to non-infectious arthroplasty failure based on analysis of transcriptomic data, but their presence in PJI-associated periprosthetic tissues has not been visually confirmed. This preliminary study investigated the presence and activation status of mast cells in periprosthetic tissues associated with PJI. Periprosthetic tissues from five PJI cases and three arthroplasty failures due to instability and one due to stiffness were immunohistochemically stained using tryptase and microscopically evaluated to enumerate mast cells and evaluate overall activation status within tissue samples. Mast cell activation was evidenced by the release of tryptase into the extracellular space surrounding mast cells. Mast cells were found in all samples, with average cellular densities of 22 and 26 cells/mm2 tissue in PJI and uninfected samples, respectively (p, 0.6610). Apparent mast cell activation and degranulation was readily observed throughout each of the five PJI samples studied, but not in any of the uninfected samples studied. While preliminary, these findings provide evidence for a role of mast cells in the immune response in PJI. Additional investigation of the role of mast cells during arthroplasty failure is warranted, providing a better understanding of underlying biology and informing potential diagnostic and treatment targets.


Right Ventricular Function at Cardiac MRI Predicts Cardiovascular Events in Patients with an Implantable Cardioverter-Defibrillator.
Background Right ventricular ejection fraction (RVEF) is an independent predictor of death and adverse cardiovascular outcomes in patients with various cardiac conditions. Purpose To investigate whether RVEF, measured with cardiac MRI, is a predictor of appropriate shock or death in implantable cardioverter-defibrillator (ICD) recipients for primary and secondary prevention of sudden cardiac death. Materials and Methods This retrospective, multicenter, observational study included patients who underwent cardiac MRI before ICD implantation between January 2007 and May 2017. Right ventricular end-diastolic and end-systolic volumes and RVEF were measured with cardiac MRI. The primary end point was a composite of all-cause mortality or appropriate ICD shock. The secondary end point was all-cause mortality. The association between RVEF and primary and secondary outcomes was evaluated by using multivariable Cox regression analysis. Potential interactions were tested between primary prevention, ischemic cause, left ventricular ejection fraction (LVEF), and RVEF. Results Among 411 patients (mean age ± standard deviation, 60 years; 315 men) during a median follow-up of 63 months, 143 (35%) patients experienced an appropriate ICD shock or died. In univariable analysis, lower RVEF was associated with greater risks for appropriate ICD shock or death and for death alone (log-rank trend test, P = .003 and .005 respectively). In multivariable Cox regression analysis adjusting for age at ICD implantation, LVEF, ICD indication (primary vs secondary), ischemic heart disease, and late gadolinium enhancement, RVEF was an independent predictor of the primary outcome (hazard ratio [HR], 1.21 per 10% lower RVEF; 95% CI: 1.04, 1.41; P = .01) and all-cause mortality (HR, 1.25 per 10% lower RVEF; 95% CI: 1.01, 1.55; P = .04). No evidence of significant interactions was found between RVEF and primary or secondary prevention (P = .49), ischemic heart disease (P = .78), and LVEF (P = .29). Conclusion Right ventricular ejection fraction measured with cardiac MRI was a predictor of appropriate implantable cardioverter-defibrillator shock or death. © RSNA, 2021 See also the editorial by Nazarian and Zghaib in this issue. An earlier incorrect version of this article appeared online. This article was corrected on August 24, 2021.


Vitamin D receptor variants and uncontrolled asthma.
Background. Asthma is a common childhood respiratory disease, affecting around 20% of Irish children. In other populations, vitamin D receptor (VDR) polymorphisms have been associated with asthma risk. We aimed to investigate the association between 2 VDR polymorphisms and uncontrolled paediatric asthma. Methods. 44 asthmatic children and 57 healthy volunteers were studied. The VDR TaqI gene variant in exon 9 (T/C) (rs731236) and ApaI (rs7975232) in intron 8 (C/T) were determined, using TaqMan® Assays. The lung function, serum 25-hydroxyvitamin D (25OHD) levels and other biomarkers of allergy, immunity, airway and systemic inflammation were as-sessed. Results. The distribution of T and C alleles and genotype frequencies differed significantly between asthmatics and controls for both polymorphisms (p < 0.05). A significant association was found between both TaqI [OR = 2.37, 95% CI (1.27 - 4.45), p = 0.007] and ApaI polymorphisms, and asthma risk [OR = 2.93, 95% CI (1.62 - 5.3), p = 0.0004]. No association was observed between genotypes and 25OHD levels, lung function and other biomarkers, with the exception of Interleukin-10 (IL-10) and white blood cells count (WBC). IL-10 levels were lower in asthmatics with TC genotype for TaqI polymorphism (p < 0.01) and were higher in patients with TT genotype for ApaI (p < 0.01). WBC were higher in patients with TC and CC genotypes for TaqI (p < 0.05) and lower in TT genotype for ApaI (p < 0.05). Conclusion. TaqI and ApaI polymorphisms are associated with asthma in Irish children. Further studies are warranted to investigate the importance of decreased IL-10 levels in paediatric asthmatics with specific genotypes.


Doxorubicin inhibits the phosphate-transport protein reconstituted in liposomes. A study on the mechanism of the inhibition.
The phosphate transport protein (PTP) has been isolated from beef heart mitochondria in the presence of cardiolipin and reconstituted in asolectin and phosphatidylcholine vesicles. As expected, the activity of the reconstituted PTP is inhibited by N-ethylmaleimide and mersalyl. It is also inhibited by adriamycin and Br-daunomycin. Storage of isolated mitochondria at -80 degrees C prior to the isolation of the PTP decreases the maximal activity of the unidirectional transport of phosphate (Pi) in reconstituted vesicles. The sensitivity of the system to the four inhibitors remains the same. The inhibition of the PTP by adriamycin is reversed by KCl and prevented by MgSO4. Since the interaction between adriamycin and cardiolipin is of ionic type, KCl apparently replaces adriamycin on the negative charges of cardiolipin. By contrast, MgSO4 complexes adriamycin directly, eliminating its inhibitory effect on the PTP. No PTP activity is found after reconstitution in phosphatidylcholine vesicles in the absence of cardiolipin. Addition of buffer-dispersed cardiolipin to the vesicles restores the Pi-transport activity. The addition of adriamycin to the vesicles together with cardiolipin removes the reactivation. Succinylation of the PTP at pH 8.0 eliminates the inhibitory effect of adriamycin in the reconstituted system. The effects of N-ethylmaleimide and mersalyl are not modified. The succinylated preparation reconstituted in phosphatidylcholine vesicles is reactivated by cardiolipin, but in this case the reactivation is not counteracted by adriamycin. Succinylation of the PTP at pH 9.0 results in its complete inhibition. The results indicate, (a) that the sites of interaction of MalNEt /mersalyl and adriamycin with the PTP X cardiolipin complex are different, and (b) that the adriamycin-binding site in the complex is probably on cardiolipin molecules essential to the PTP activity. It is postulated that succinylation of the PTP prevents the interaction of adriamycin with these molecules.


Actinomyces israelii in the genital tract of women with and without intra-uterine contraceptive devices.
Actinomycosis involving the female genital tract is more common among IUD users than others. The diagnosis is difficult and often delayed. It has been suggested that the finding of Actinomyces-like organisms or A. israelii in cervical smears indicates a risk of developing actinomycosis. A. israelii has not been regarded as a part of the indigenous genital flora. A group of IUD users without symptoms of genital tract infections were compared with a control group without IUDs. No Actinomyces-like organisms were found on cytological examination of cervical smears. Immunofluorescent staining and cultures identified A. israelii in 4% of the IUD users and in 3% of the non-users. Serologic precipitin tests for actinomycosis were negative in all women. None developed actinomycosis on follow-up of positive cases. The study indicates that A. israelii is a commensal of the female genital tract. The identification of A. israelii alone does not indicate that the patient risks developing actinomycosis. Other methods such as a serology test should be useful in defining the clinical significance of the findings.


An additive destabilising effect of compound T60I and V122I substitutions in ATTRv amyloidosis.
The amyloidogenic transthyretin (TTR) variant, V122I, occurs in 4% of the African American population and frequently presents as a restricted cardiomyopathy. While heterozygosity for TTR V122I predominates, several compound heterozygous cases have been previously described. Herein, we detail features of ATTRv amyloidosis associated with novel compound heterozygous TTR mutation, T60I/V122I and provide evidence supporting the amyloidogenecity of T60I. A 63-year-old African American female presented with atrial fibrillation, congestive heart failure, autonomic and peripheral neuropathy. In vitro studies of TTR T60I and V122I were undertaken to compare the biophysical properties of the proteins. Congophilic deposits in a rectal biopsy were immunohistochemically positive for TTR. Serum screening by isoelectric focussing revealed two TTR variants in the absence of wild-type protein. DNA sequencing identified compound heterozygous TTR gene mutations, c.239C > T and c.424G > A. Adipose amyloid deposits were composed of both T60I and V122I. While kinetic stabilities of T60I and V122I variants were similar, distinct thermodynamic stabilities and amyloid growth kinetics were observed. This report provides clinical and experimental results supporting the amyloidogenic nature of a novel TTR T60I variant. In vitro data indicate that the destabilising effect of individual T60I and V122I variants appears to be additive rather than synergistic.


Comparison of the STYCAR and lighthouse acuity tests.
In a study comparing the Screening Test for Young Children and Retardates (STYCAR) and the New York Lighthouse Flash Card Test, 50 preschool children (median age of 4.4 yr) were evaluated twice with each instrument. Results indicate that the Lighthouse test had higher reliability, better visual acuity scores, lower untestability rates, and shorter testing times than the STYCAR.


Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome.
Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity.


[Active management of labor in Dublin: what is it 15 years later?].
Every obstetrician, in his readings, must have come across a report of article by K. O'Driscoll, and could not remain indifferent (surprise, incredulity, even anger...) in front of astonishing results: 5% of caesarean sections, 5 to 6% of forceps deliveries, combined with a recruiting worthy of any large university center and creditable neonatal results which are accurately analysed. In view of the difficulty and understanding of the basis of "active management of labor", advocated by this team and described as the main reason of its success, the author tried to understand, while staying in this department, the highlights of its daily obstetrical practice. In this detailed report of the activities of this irish obstetrical team, the author wanted to put the results back in their context and broadly outline the organization of this department and the management of labor, in order to evaluate the significance of the figures reported in numerous international publications and too often not easy to analyse for uninformed readers.


Evaluation of the time-concentration-mortality responses of Plutella xylostella larvae to the interaction of Beauveria bassiana with a nereistoxin analogue insecticide.
Six bioassays were conducted to evaluate the interaction between Beauveria bassiana SG8702 and a nereistoxin analogue insecticide, diammonium S,S'-(2-dimethylaminotrimethylene)di(thiosulfate), which is highly compatible with the fungal biocontrol agent against diamondback moth Plutella xylostella (L.). Second-instar larvae were exposed to sprays of B. bassiana alone (assay 1) at concentrations of 21-38, 157-232 and 822-1133 conidia mm(-2) or together with the insecticide at the low application rates of 5, 10, 25, 50 and 100 microg AI ml(-1) (assays 2-6), and then maintained at 25 degrees C and 12:12 h light:dark photoperiod for daily monitoring of mortality for 8 days. Based on the modelling of the resultant time-concentration-mortality data sets, the fungal agent was highly virulent to P. xylostella with an LC50 decreasing from 269 conidia mm(-2) on day 4 to 107 on day 8. Lower lethal concentrations or shorter median lethal times resulted from fungal sprays including the tested chemical rates; the latter never caused higher mortalities than the fungal treatments alone. The fungal action over 3-7 days after spray was significantly enhanced by including in the fungal sprays the chemical at rates of > or =25 microg ml(-1) for 2.6- to 1756-fold reduction of LC50 values, > or =50 microg ml(-1) for 4- to 274-fold reduction of LC70 values and 100 microg ml(-1) for 9- to 33-fold reduction of LC90 values respectively. These rates were equivalent to 5-20% of the chemical rate labelled for field application. The fungal and chemical interaction outlined above highlights the feasibility of combined formulation or application of B. bassiana and the chemical insecticide for P. xylostella control.


The systolic-diastolic difference in carotid stiffness is increased in type 2 diabetes: The Maastricht Study.
In type 2 diabetes (T2D), increased arterial stiffening results from accelerated arterial wall matrix remodeling. The associated structural alterations modify the pressure dependency of arterial stiffness, which can be quantified by the systolic-diastolic difference in carotid pulse wave velocity (δPWV). We evaluated the association between T2D and δPWV as marker for matrix remodeling and whether δPWV may contain additional information beyond carotid stiffness (cPWV). In 746 individuals from The Maastricht Study, 415 with normal glucose metabolism; 126 with prediabetes; and 205 with T2D, carotid pulse wave velocity (cPWV) and δPWV were determined by ultrasonography and tonometry. Multiple linear regression analyses were used to investigate associations of glucose metabolism status (with normal glucose metabolism as reference) with cPWV and δPWV, adjusting for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, and δPWV or cPWV as appropriate. After adjustment for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, T2D was associated with greater cPWV [β (95% confidence interval) 0.376 (0.119; 0.632)] and δPWV [0.301 (0.013; 0.589)]. After additional adjustment for δPWV or cPWV, associations of T2D with cPWV and δPWV were attenuated [0.294 (0.048; 0.539) and 0.173 (-0.103; 0.449), respectively]. Prediabetes was not associated with either cPWV or δPWV. The systolic-diastolic difference in carotid stiffness is increased in T2D, but not prediabetes. Importantly, the association was not abolished by carotid stiffness, which suggests that systolic-diastolic difference in carotid stiffness carries additional information regarding arterial matrix remodeling.


Hypertension with unsatisfactory sleep health (HUSH): study protocol for a randomized controlled trial.
Insomnia is common in primary care medical practices. Although behavioral treatments for insomnia are safe, efficacious, and recommended in practice guidelines, they are not widely-available, and their effects on comorbid medical conditions remain uncertain. We are conducting a pragmatic clinical trial to test the efficacy of two cognitive behavioral treatments for insomnia (Brief Behavioral Treatment for Insomnia (BBTI) and Sleep Healthy Using the Internet (SHUTi)) versus an enhanced usual care condition (EUC). The study is a three-arm, parallel group, randomized controlled trial. Participants include 625 adults with hypertension and insomnia, recruited via electronic health records from primary care practices affiliated with a large academic medical center. After screening and baseline assessments, participants are randomized to treatment. BBTI is delivered individually with a live therapist via web-interface/telehealth sessions, while SHUTi is a self-guided, automated, interactive, web-based form of cognitive behavioral therapy for insomnia. Participants in EUC receive an individualized sleep report, educational resources, and an online educational video. Treatment outcomes are measured at 9 weeks, 6 months, and 12 months. The primary outcome is patient-reported sleep disturbances. Secondary outcomes include other self-reported sleep measures, home blood pressure, body mass index, quality of life, health functioning, healthcare utilization, and side effects. This randomized clinical trial compares two efficacious insomnia interventions to EUC, and provides a cost-effective and efficient examination of their similarities and differences. The pragmatic orientation of this trial may impact sleep treatment delivery in real world clinical settings and advance the dissemination and implementation of behavioral sleep interventions. ClinicalTrials.gov (Identifier: NCT02508129 ; Date Registered: July 21, 2015).


[METHODOLOGICAL APPROACHES TO THE FORMATION OF THE RATING OF THE CONSTITUENT ENTITIES OF THE RUSSIAN FEDERATION, REFLECTING THE EFFICIENCY AND QUALITY OF MEDICAL CARE BY PROFILE].
Aim of the study - determination of approaches to the formation of the rating of the constituent entities of the Russian Federation, reflecting the state of medical care in various profiles (the effectiveness and quality of medical care in various profiles). The study included a comprehensive analysis of the structure and content of the reports based on the results of national medical research centers field events using classification and grouping methods. Assessment of the advantages and disadvantages of the used variants of the methodology for forming the subject rating of the Russian Federation used the method of selective SWOT analysis of methodologies published in the form of scientific articles. Further, based on the results obtained, the main requirements for building a rating system for subjects of the Russian Federation based on the indicators of efficiency (performance) and the quality of medical care were formulated. The possibility of applying international experience in building benchmarking systems in the Russian Federation is analyzed and requirements are formulated for building a subject rating system of the Russian Federation, taking into account the peculiarities of the domestic healthcare system. There are 3 main methodological approaches to the formation of the subject rating of the Russian Federation: a quantitative score rating assessment of quantitative indicators without weight coefficients, a qualitative rating assessment of the effectiveness of medical care in a profile without weight coefficients, and a mixed score-rating assessment of quantitative and qualitative indicators using weight coefficients determined only by an expert method. It has been established that many of the existing approaches to the formation of the subject rating of the Russian Federation are based on a combination of a point rating and weight coefficients established by an expert method. Since different indicators have different contributions to the final integral value of the subject rating of the Russian Federation, it is advisable to conduct another study to establish weight coefficients for indicators.


Elevated serum tryptase level in a case of intraoperative anaphylaxis caused by latex allergy.
We measured serial serum tryptase levels in a case of intraoperative anaphylaxis caused by allergy to latex. The serum tryptase level was elevated 7 hours after the hypotensive episode and returned to normal after recovery 4 months later. Both skin tests to latex and serum IgE to latex confirmed latex allergy in this patient. To our knowledge, this is the first report of an elevated serum tryptase level in intraoperative anaphylaxis caused by latex allergy. This observation confirms the role of mast cell degranulation in anaphylaxis caused by allergy to latex.


Fast apixaban-related resolution of left ventricular thrombi in a patient with dilated cardiomyopathy.
Left ventricular thrombi (LVTs) develop most often in patients with post-myocardial left ventricular dysfunction and in cardiomyopathies, particularly in dilated cardiomyopathy (DCM). They constitute a danger of systemic embolization. So far, direct-acting oral anticoagulants (DOACs), including apixaban - a selective inhibitor of active Factor X, have not been systematically investigated in patients with LVTs; study comparing the efficacy of apixaban and warfarin has been undertaken only recently. A few case reports or case series presenting patients with LVTs treated with DOACs are available in the literature. The authors described a case of a 53-year-old male with DCM, hospitalized due to heart failure exacerbation. In echocardiography, apart from typical features of DCM, three apical LVTs connected with false tendons were revealed. Treatment with apixaban was introduced, initially in a dose of 2.5 mg twice daily, as creatinine concentration was 2.0 mg/dl, and after 2 days - when creatinine concentration dropped, the dose was augmented to 5 mg twice a day. Gradual resolution of LVTs was observed from day 3; they disappeared completely after one week. There were no symptoms of systemic embolization. The patient was discharged with advice to take apixaban permanently. To the best of the authors knowledge, the case presented is the fastest resolution of LVTs during therapy with apixaban reported in the literature and the first description of DOAC use for multiple LVTs.


Pregnant Nigerian woman's view of her prenatal sex determination.
A questionnaire survey was conducted among 1000 pregnant Nigerian women to identify their knowledge and perception of prenatal sex determination using ultrasonography. Eighty-one per cent of the respondents were aware of the technology. Knowledge of it was associated with high parity and education. However, only 64% of respondents desired to know the sex of their fetus. Younger age, low parity and less number of existing male children influenced this desire. There was no indication of considering possible abortion of the fetus if the identified sex was not the desired one. It is suggested that as there seem no grave sequelae of revealing the sex of the fetus, sonologists should not withhold this information from mothers if they so desire.


Long-term survivors in chronic granulocytic leukaemia: a study by the International CGL Prognosis Study Group. Italian Cooperative CML Study Group.
The purpose of the present work were to identify the initial characteristics associated with long-term survival in chronic granulocytic leukaemia (CGL) and to analyse the accuracy of prognostic models in identifying long-term survivors. 813 Philadelphia (Ph) chromosome-positive, nonblastic CGL patients from six American and European institutions, the majority treated conventionally, with a minimum follow-up > 10 years, were studied. Stepwise logistic regression was performed to ascertain the association between the initial clinicohaematological variables and survival > or = 8 years, and a prognostic index was derived. The usefulness of both Sokal's and the new prognostic index to identify long-term survivors was assessed by calculating their positive and negative predictive accuracies, sensitivity and specificity. Median survival of the series was 45 months (range 1-255), with 784 patients (96.4%) having died and 109 (13.4%) surviving 8 years or longer. Younger age, smaller spleen, platelets < or = 600 x 10(9)/l, and lower blood blast percentage were associated with survival > or = 8 years; platelets < or = 600 x 10(9)/l and lower blood blast percentage were the predictive factors in patients 50 years old or younger. Two-thirds of long survivors belonged to Sokal's low-risk group, but the positive predictive accuracy and specificity for prolonged survival of Sokal's index were very low. This was also the case for the new predictive index.(ABSTRACT TRUNCATED AT 250 WORDS)


[An investigation of extracellular HER-2/NEU domain level in blood serum from breast cancer patients].
A series of 159 tests on HER2 ECD in blood serum from breast cancer patients established the following correlations: enhanced levels of the marker occurred more often in patients with multiple metastases to different organs alongside those with bone metastases; patients in loco-regional relapse tended to show elevated levels too. It is suggested that the method be used for prognosis and monitoring.


[The first decades of pharmaceutical training at the Royal Hungarian University in the XVIIIth century].
This is the second part of the author's former article; the previous one was published in the last issue of our journal. The author gives an overview on the education of pharmacists in 18th-century Hungary. She attempts to provide a complete list of the sources of medical and pharmaceutical education, with a special regard on subjects lacking any textbook published in Hungary at that time. Based on the analysis of hand-written and archival data author concludes that students during their courses borrowed the required exsiccated material or manuscripts and even the herbal items from the University itself. Author calls our attention to the hitherto neglected fact, that the possibility of acquiring botanical knowledge was actually given at the University, while former researches emphasized only the difficulties. Even the library of the university at Buda and Pest possessed a rather valuable material. Author concludes, that the pharmaceutical education in Hungary presented the average level of the age.


Nucleocytoplasmic lectins.
This review summarizes studies on lectins that have been documented to be in the cytoplasm and nucleus of cells. Of these intracellular lectins, the most extensively studied are members of the galectin family. Galectin-1 and galectin-3 have been identified as pre-mRNA splicing factors in the nucleus, in conjunction with their interacting ligand, Gemin4. Galectin-3, -7, and -12 regulate growth, cell cycle progression, and apoptosis. Bcl-2 and synexin have been identified as interacting ligands of galectin-3, involved in its anti-apoptotic activity in the cytoplasm. Although the annexins have been studied mostly as calcium-dependent phospholipid-binding proteins mediating membrane-membrane and membrane-cytoskeleton interactions, annexins A4, A5 and A6 also bind to carbohydrate structures. Like the galectins, certain members of the annexin family can be found both inside and outside cells. In particular, annexins A1, A2, A4, A5, and A11 can be found in the nucleus. This localization is consistent with the findings that annexin A1 possesses unwinding and annealing activities of a helicase and that annexin A2 is associated with a primer recognition complex that enhances the activity of DNA polymerase alpha. Despite these efforts and accomplishments, however, there is little evidence or information on an endogenous carbohydrate ligand for these lectins that show nuclear and/or cytoplasmic localization. Thus, the significance of the carbohydrate-binding activity of any particular intracellular lectin remains as a challenge for future investigations.


Poor phenotype-genotype association in a large series of patients with Type III Bartter syndrome.
Type III Bartter syndrome (BS) is an autosomal recessive renal tubule disorder caused by loss-of-function mutations in the CLCNKB gene, which encodes the chloride channel protein ClC-Kb. In this study, we carried out a complete clinical and genetic characterization in a cohort of 30 patients, one of the largest series described. By comparing with other published populations, and considering that 80% of our patients presented the p.Ala204Thr Spanish founder mutation presumably associated with a common phenotype, we aimed to test the hypothesis that allelic differences could explain the wide phenotypic variability observed in patients with type III BS. Clinical data were retrieved from the referral centers. The exon regions and flanking intronic sequences of the CLCNKB gene were screened for mutations by polymerase chain reaction (PCR) followed by direct Sanger sequencing. Presence of gross deletions or duplications in the region was checked for by MLPA and QMPSF analyses. Polyuria, polydipsia and dehydration were the main common symptoms. Metabolic alkalosis and hypokalemia of renal origin were detected in all patients at diagnosis. Calciuria levels were variable: hypercalciuria was detected in 31% of patients, while 23% had hypocalciuria. Nephrocalcinosis was diagnosed in 20% of the cohort. Two novel CLCNKB mutations were identified: a small homozygous deletion (c.753delG) in one patient and a small deletion (c.1026delC) in another. The latter was present in compound heterozygosis with the already previously described p.Glu442Gly mutation. No phenotypic association was obtained regarding the genotype. A poor correlation was found between a specific type of mutation in the CLCNKB gene and type III BS phenotype. Importantly, two CLCNKB mutations not previously described were found in our cohort.


Evaluating the Usability and Usefulness of a Mobile App for Atrial Fibrillation Using Qualitative Methods: Exploratory Pilot Study.
Atrial fibrillation (AFib) is the most common form of heart arrhythmia and a potent risk factor for stroke. Nonvitamin K antagonist oral anticoagulants (NOACs) are routinely prescribed to manage AFib stroke risk; however, nonadherence to treatment is a concern. Additional tools that support self-care and medication adherence may benefit patients with AFib. The aim of this study was to evaluate the perceived usability and usefulness of a mobile app designed to support self-care and treatment adherence for AFib patients who are prescribed NOACs. A mobile app to support AFib patients was previously developed based on early stage interview and usability test data from clinicians and patients. An exploratory pilot study consisting of naturalistic app use, surveys, and semistructured interviews was then conducted to examine patients' perceptions and everyday use of the app. A total of 12 individuals with an existing diagnosis of nonvalvular AFib completed the 4-week study. The average age of participants was 59 years. All participants somewhat or strongly agreed that the app was easy to use, and 92% (11/12) reported being satisfied or very satisfied with the app. Participant feedback identified changes that may improve app usability and usefulness for patients with AFib. Areas of usability improvement were organized by three themes: app navigation, clarity of app instructions and design intent, and software bugs. Perceptions of app usefulness were grouped by three key variables: core needs of the patient segment, patient workflow while managing AFib, and the app's ability to support the patient's evolving needs. The results of this study suggest that mobile tools that target self-care and treatment adherence may be helpful to AFib patients, particularly those who are newly diagnosed. Additionally, participant feedback provided insight into the varied needs and health experiences of AFib patients, which may improve the design and targeting of the intervention. Pilot studies that qualitatively examine patient perceptions of usability and usefulness are a valuable and often underutilized method for assessing the real-world acceptability of an intervention. Additional research evaluating the AFib Connect mobile app over a longer period, and including a larger, more diverse sample of AFib patients, will be helpful for understanding whether the app is perceived more broadly to be useful and effective in supporting patient self-care and medication adherence.


Combination of deep learning and ensemble machine learning using intraoperative video images strongly predicts recovery of urinary continence after robot-assisted radical prostatectomy.
We recently reported the importance of deep learning (DL) of pelvic magnetic resonance imaging in predicting the degree of urinary incontinence (UI) following robot-assisted radical prostatectomy (RARP). However, our results were limited because the prediction accuracy was approximately 70%. To develop a more precise prediction model that can inform patients about UI recovery post-RARP surgery using a DL model based on intraoperative video images. The study cohort comprised of 101 patients with localized prostate cancer undergoing RARP. Three snapshots from intraoperative video recordings showing the pelvic cavity (prior to bladder neck incision, immediately following prostate removal, and after vesicourethral anastomosis) were evaluated, including pre- and intraoperative parameters. We evaluated the DL model plus simple or ensemble machine learning (ML), and the area under the receiver operating characteristic curve (AUC) was analyzed through sensitivity and specificity. Of 101, 64 and 37 patients demonstrated "early continence (using 0 or 1 safety pad at 3 months post-RARP)" and "late continence (others)," respectively, at 3 months postoperatively. The combination of DL and simple ML using intraoperative video snapshots with clinicopathological parameters had a notably high performance (AUC, 0.683-0.749) to predict early recovery from UI after surgery. Furthermore, combining DL with ensemble artificial neural network using intraoperative video snapshots had the highest performance (AUC, 0.882; sensitivity, 92.2%; specificity, 78.4%; overall accuracy, 85.3%) to predict early recovery from post-RARP incontinence, with similar results by internal validation. The addition of clinicopathological parameters showed no additive effects for each analysis using DL, EL and simple ML. Our findings suggest that the DL algorithm with intraoperative video imaging is a reliable method for informing patients about the severity of their recovery from UI after RARP, although it is not clear if our methods are reproducible for predicting long-term UI and pad-free continence.


Identifying Therapeutic Targets for Spinocerebellar Ataxia Type 3/Machado-Joseph Disease through Integration of Pathological Biomarkers and Therapeutic Strategies.
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function.


The Hydraulic Mechanism in the Orbital Blowout Fracture Because of a High-Pressure Air Gun Injury.
There are 2 predominant mechanisms that are used to explain the pathogenesis of orbital blowout fracture; these include hydraulic and buckling mechanisms. Still, however, its pathophysiology remains uncertain. To date, studies in this series have been conducted using dry skulls, cadavers, or animals. But few clinical studies have been conducted to examine whether the hydraulic mechanism is involved in the occurrence of pure orbital blowout fracture. The authors experienced a case of a 52-year-old man who had a pure medial blowout fracture after sustaining an eye injury because of a high-pressure air gun. Our case suggests that surgeons should be aware of the possibility that the hydraulic mechanism might be involved in the blowout fracture in patients presenting with complications, such as limitation of eye movement, diplopia, and enophthalmos.


High-flow nasal cannula in the treatment of acute hypoxemic respiratory failure in a pregnant patient: case report.
Little evidence exists to support the use of noninvasive mechanical ventilation for acute hypoxemic respiratory failure. However, considering the complications associated with endotracheal intubation, we attempted to implement noninvasive mechanical ventilation in a 24-year-old patient who was 32 weeks pregnant and was admitted to the intensive care unit with acute hypoxemic respiratory failure and sepsis secondary to a urinary tract infection. Lack of tolerance to noninvasive mechanical ventilation led us to use an alternative method to avoid endotracheal intubation. The use of high-flow nasal cannula allowed to overcome this situation, wich supports this technique as a treatment option for critical obstetric patients that is safe for both the mother and fetus.


Triplet Chemotherapy (FOLFOXIRI) Plus Bevacizumab Versus Doublet Chemotherapy (FOLFOX/FOLFIRI) Plus Bevacizumab in Conversion Therapy for Metastatic Colorectal Cancer: a Meta-Analysis.
Conversion therapy can convert unresectable metastatic colorectal cancer (mCRC) into resectable. However, the optimal conversion regimen was not yet defined. This meta-analysis aimed to compare the efficacy and safety of the triplet chemotherapy (FOLFOXIRI) plus bevacizumab (Bev) with doublet chemotherapy (FOLFOX/FOLFIRI) plus Bev in conversion therapy. Randomized controlled trials (RCTs) from databases, including Pubmed, EMBASE, Cochrane clinical trials, clinicaltrial.gov and some conferences, were searched from the inception to November 2017. The R0 resection, objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and the incidence of adverse events were pooled with the use of hazard ratio (HR) or risk ratio (RR). Four RCTs with 1013 patients were included. FOLFOXIRI plus Bev regimen significantly improved the overall R0 resection rate (RR 1.41, 95% confidence interval (CI) 1.07-1.85, I2=37%), liver R0 resection rate (RR 2.28, 95% CI 1.34-3.89, I2=0%), ORR (RR 1.20, 95% CI 1.09-1.32, I2=0%), PFS (HR 0.72, 95% CI 0.62-0.84, I2=36%) and OS (HR 0.80, 95% CI 0.66-0.97, I2=0%). There was no significant difference in any Grade≥3 adverse event (RR 1.08, 95% CI 0.99-1.17, I2=0%) between two regimens. FOLFOXIRI-Bev was associated with a higher risk of neutropenia (RR 1.77, 95% CI 1.13-2.79, I2=68%) and diarrhea (RR 1.65, 95% CI 1.17-2.32, I2=0%). Triplet chemotherapy plus Bev significantly improved the R0 resection rates, ORR, PFS and OS in comparison with doublet chemotherapy plus Bev in conversion therapy for mCRC patients, with a higher risk of neutropenia and diarrhea.


New competency framework for emergency nurses.
A competency framework for emergency nurses and those wanting a career in the role has been launched in an effort to aid recruitment and retention.


Long-term follow-up of the incisional hernia rate after single-incision laparoscopic cholecystectomy: a prospective observational study.
To evaluate the long-term occurrence rate of incisional hernias following single-incision laparoscopic cholecystectomy (SILC). Since the 90 s, SILC has emerged as a less invasive alternative to standard laparoscopic cholecystectomy in selected patients. But concerns over port-incisional hernias have not been addressed. Between February 2009 and February 2011, 142 patients referred for gallstones who agreed to undergo SILC were included in a monocenter prospective observational study. All of the procedures were carried out using a single-port access technique. The occurrence rates of incisional hernias were analyzed with the Kaplan-Meier actuarial method. Statistical significance was set at p < .05. A total of 142 patients with gallbladder pathology were included in the study; 138 of them underwent SILC and 4 were converted to standard multiport cholecystectomy. Twelve patients (8%) were found to have developed a port-site incisional hernia (PSH) by physical examination or by imaging. The Kaplan-Meier curve showed that the rate of PSH development was 83% in the first 2 years after surgery. After 2 years, this risk becomes quite low. Our results indicate that the SILC procedure is a safe option for treatment of benign gallbladder diseases for selected patients, albeit with a high incisional hernia rate.


Management of compartment syndromes of the foot.
Twelve patients with isolated extremity injuries had 14 compartment syndromes of the feet. An interstitial pressure of more than 30 mm of mercury in either the central or interosseous compartment was considered pathologic and was treated by fasciotomy, performed dorsally in nine feet and medially in five. Open reduction of fractures amenable to internal fixation (eight tarsometatarsal, three calcaneus, and one metatarsal) was performed after completion of the fasciotomies. The fasciotomy wounds were covered by primary split-thickness skin excision (three), delayed split-thickness skin grafting (eight), and delayed primary wound closure (three). Patients were evaluated at a mean of 22 months (range, 17-36 months) after injury, and the examination was directed specifically toward symptoms and signs of myoneural ischemia. Absolute compartment pressure measurements are more accurate than clinical findings in the diagnosis of a compartment syndrome of the foot. Fasciotomy may be performed medially or dorsally, depending on the configuration of the pattern of fracture or dislocation. To ensure satisfactory results, all compartments should be decompressed, and the pressures remeasured after the completion of fasciotomy.


Clinical Trial Design Using A Stopped Negative Binomial Distribution.
We introduce a discrete distribution suggested by curtailed sampling rules common in early-stage clinical trials. We derive the distribution of the smallest number of independent and identically distributed Bernoulli trials needed to observe either s successes or t failures. This report provides a closed-form expression for the mass function, moment generating function, and provides connections to other, standard distributions.