Growth hormone therapy and children with idiopathic short stature: a viable option?
Since the production of biosynthetic growth hormone (GH) began in 1985, there has been growing controversy over appropriate usage for short stature alone. Despite clinical trials for nearly 2 decades, knowledge about the efficacy, safety, and long-term results of GH for this population remains limited. So far, studies of children without growth hormone deficiency (GHD) have found an initial acceleration in growth, but no increase in adult height above pretreatment target height percentiles. Additionally, recent studies have been unable to link normal short stature with adverse psychological effects, while use of GH therapy has been associated with an exacerbation of problems. Thus, there is evidence that GH therapy does not provide the means to overcome either the physical or psychosocial dilemmas of short stature. Health care providers need to recognize the complexity of problems surrounding short stature and look to other "solutions."


Antimicrobial sesquiterpene lactones from Artemisia sieberi.
Two new sesquiterpene lactones 3R, 8R-dihydroxygermacr-4(15),9(10)-dien-6S,7S,11RH,12,6-olide (1) and 1R, 8S-dihydroxy-11R,13-dihydrobalchanin(2), together with two known compounds 11-epiartapshin (3) and 3'-hydroxygenkwanin (4), were isolated from Artemisia sieberi. Their structures were elucidated by 1D, 2D NMR, MS, and X-ray diffraction. Compound 4 inhibited Gram-positive bacteria Bacillus subtilis and Staphylococcus aureus with Minimal inhibitory concentration values of 50 and 25 μg/disk, respectively. All the isolated compounds exhibited moderate antifungal activities.


Nationwide survey of neurologic manifestations of acquired immunodeficiency syndrome in Japan.
To study the epidemiology of the neurologic manifestations of human immunodeficiency virus (HIV)-1 infection in Japan, we conducted two nationwide surveys. Of 1854 HIV-1 carriers, 578 had acquired immunodeficiency syndrome (AIDS) and 166 (28.7% of AIDS patients) had neurologic manifestations including HIV dementia (11.8%), myelopathy (3.6%) and peripheral neuropathy (2.6%). The incidence of neurologic manifestations in patients with HIV-1 infection through blood products was about 60% of that in patients with HIV-1 infection through sex or unknown routes. This nationwide survey showed that the incidence of neurologic manifestations in AIDS patients in Japan was consistent with that in other countries.


Clinical utility of fetal echocardiography: an Egyptian center experience.
The impact of early diagnosis of fetal cardiac abnormalities on the postnatal outcome has been controversial in literature. We aimed to evaluate the role of fetal echocardiography (FE) as a diagnostic tool for early detection and proper management of fetal cardiac abnormalities, study the indications of referral and detect the perinatal outcome in our institution. This is a cross-sectional observational and descriptive study that included one hundred and one singleton pregnant women (101 fetuses) who were referred for FE over a period of one year. Indications for referral and perinatal risk factors were documented. FE and postnatal transthoracic echocardiography were done. Fetal cardiac abnormalities were detected in 46.5% of cases. Congenital heart defects (CHDs) in 34.6%, fetal arrythmias in 9.9%, cardiomyopathy in 2.9% and cardiac mass (Rhabdomyoma) in 1% (combined structural and rhythm abnormalities were observed in two fetuses). Of the CHDs, complex heart lesions were diagnosed in 57.1%, common atrioventricular canal in 28.6% and conotrunchal anomalies in 14.3%. Of the ten cases with fetal arrythmias, five fetuses had tachyarrhythmias, four had ectopics and one fetus had congenital heart block in association with maternal lupus. The indications for referral were abnormal obstetric ultrasound (52.5%), maternal medical illnesses (23.8%), multiple neonatal deaths (13.9%) and positive family history of CHD (10.9%). The number of fetuses with cardiac abnormalities was significantly higher than those without cardiac abnormalities in mothers not exposed to perinatal risk factors (p = 0.009) and was statistically lower in mothers exposed to perinatal risk factors (p = 0.005). FE showed 100% accuracy in diagnosing complex lesions, common atrio-ventricular canals, cono-truncal anomalies, cardiac masses and fetal arrhythmias. It missed two cases of tiny muscular ventricular septal defects and one case of aortic coarctation. Cases of fetal supraventricular tachycardia were successfully treated in-utero. CHDs exist in fetuses with no underlying perinatal risk factors. FE can accurately diagnose most of the cardiac anomalies though few errors remain challenging (aortic coarctation). It also offers a good chance for successful early life-saving management of some types of fetal arrhythmia.


Legionella--every infection preventionist's dream--or is it?
Legionella is an underreported disease challenge within the hospital setting. In order to combat Legionella during times of construction and renovation, infection preventionists must become construction experts. The infection preventionist must be able to plan for potential waterborne disease outbreaks and protect the hospital staff, patients and visitors from waterborne pathogens. Legionella's history, signs and symptoms, diagnostic testing and treatment will be discussed. The hospital's convening of a multidisciplinary Legionella task force to work cohesively to develop a waterborne pathogens plan will also be discussed. This article was written from the perspective of the infection preventionist and employee health nurse at the time of the Legionella outbreak at their hospital.


Regulation of the Klebsiella pneumoniae Kpc fimbriae by the site-specific recombinase KpcI.
In the genome of Klebsiella pneumoniae NTUH-K2044, nine fimbrial gene clusters were identified. Besides type 1 and type 3 fimbriae, the others are novel and were named Kpa, Kpb, Kpc, Kpd, Kpe, Kpf and Kpg fimbriae. Prevalence analysis among 105 K. pneumoniae clinical isolates revealed that the kpc genes were highly associated with the K1 serotype isolates. Induced expression of the recombinant kpcABCD genes in Escherichia coli resulted in Kpc fimbriation and increased biofilm formation. A putative site-specific recombinase encoding gene kpcI and a 302 bp intergenic DNA flanked by 11 bp inverted repeats, namely kpcS, were identified in the upstream region of the kpcABCD genes. Using LacZ as the reporter, a dramatic difference in promoter activity of kpcS in two different orientations was observed and accordingly assigned as ON and OFF phase. kpcI expression was found to be able to invert kpcS in trans from phase ON to OFF and vice versa. Using the two-plasmid system, expression of kpcA, encoding the major component of the Kpc fimbriae, could be observed upon the induced expression of kpcI. These results indicate that KpcI is involved in the regulation of Kpc fimbriation in a phase-variable manner.


Early infant diagnosis and outcomes in HIV-exposed infants at a central and a district hospital, Northern Malawi.
Setting: Mzuzu Central Hospital (MZCH), Mzuzu, and Chitipa District Hospital (CDH), Chitipa, Malawi. Objective: To compare management and outcomes of human immunodeficiency virus (HIV) exposed infants in early infant diagnosis (EID) programmes at MZCH, where DNA polymerase chain reaction (PCR) testing is performed on site, and CDH, where samples are sent to MZCH, between 2013 and 2014. Design: Retrospective cohort study. Results: Of infants enrolled at MZCH (n = 409) and CDH (n = 176), DNA PCR results were communicated to the children's guardians in respectively 56% and 51% of cases. The median time from sample collection to guardians receiving results was 34 days for MZCH and 56 days for CDH. In both hospitals, only half of the dried blood spot (DBS) samples were collected between 6 and 8 weeks. More guardians from MZCH than CDH received test results within 1 month of sample collection (25% vs. 10%). Among the HIV-positive infants, a higher proportion at MZCH (92%) started antiretroviral therapy than at CDH (46%). The relative risk (RR) of death was higher among infants with late DBS collection (RR 1.3, 95%CI 1.0-1.7) or no collection (RR 5.8, 95%CI 4.6-7.2), and when guardians did not receive test results (RR 8.3, 95%CI 5.7-11.9). Conclusion: EID programmes performed equally poorly at both hospitals, and might be helped by point-of-care DNA PCR testing. Better programme implementation and active follow-up might improve infant outcome and retention in care.


Perivascular epithelioid cell tumour (PEComa) of the soft tissue.
PEComa is a rare tumour developing from perivascular epithelioid cells (PEC) and is characterised by positive immunoreactivity for HMB45. Since PEComas are tumours having both a spindle cell component and an epithelioid and giant cell component, as seen in many sarcomas, as well as having a wide distribution in various organs and soft tissue, we reviewed cases originally diagnosed as sarcomas of the soft tissue in our institution and screened them by immunostaining for HMB45. Consecutive soft tissue sarcomas (31 tumours) retrieved from the Surgical Pathology file at our institution for a period of 3 years were submitted for immunostaining for HMB45. Cases with positive HMB45 immunostaining were submitted for further immunostaining for MART1, CD68, S100 protein, cytokeratin AE1/3, EMA, vimentin, MSA and CD117. Of 31 sarcomas, three tumours in the group of 11 malignant fibrous histiocytomas (MFH) and unclassified sarcomas showed positive immunoreactivity for HMB45 and MART1 in 1-25% of tumour cells. The three tumours were located in the lower extremities and measured 8, 11 and 12 cm in diameter. Patient gender male:female was 2:1 and ages were 46, 56 and 60 years. Microscopically, the tumours were composed of a variable proportion of spindled cells, multinucleated cells and epithelioid cells disposed in diffuse sheets or nests. Mitotic figures and necrosis were frequent. The immunoreactivity was diffuse for CD68, focal for AE3 and EMA, negative or focal for MSA and CD117, and negative for S100 and AE1. All three patients developed lymph node or distant metastases and died of the disease within 1-2 years. PEComa re-screened from the group of high grade sarcomas without definite differentiation range from pleomorphic to monomorphic cytohistopathological features. Immunostaining for HMB45 of unclassified sarcomas is useful for the classification of these tumours. They occur preferentially in the lower extremities and have a high malignant potential when associated with large size, tumoural necrosis and high mitotic activity.


Identification of novel TMPRSS2 inhibitors against SARS-CoV-2 infection: a structure-based virtual screening and molecular dynamics study.
The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks are helping scientists to fast-track the antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses, as well as influenza viruses, depend on host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation in the human cell. Recent studies show that SARS-CoV-2 also uses TMPRSS2 for its cell entry. In the present study, a structure-based virtual screening of 52,337, protease ligands downloaded from the Zinc database was carried out against the homology model of TMPRSS2 protein followed by the molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening has identified 13 hits with a docking score range of -10.447 to -9.863 and glide energy range of -60.737 to -40.479 kcal/mol. The binding mode analysis shows that the hit molecules form H-bond (Asp180, Gly184 & Gly209), Pi-Pi stacking (His41), and salt bridge (Asp180) type of contacts with the active site residues of TMPRSS2. In the MD simulation of ZINC000013444414, ZINC000137976768, and ZINC000143375720 hits show that these molecules form a stable complex with TMPRSS2. The complex equilibrates well with a minimal RMSD and RMSF fluctuation. All three structures, as predicted in Glide XP docking, show a prominent interaction with the Asp180, Gly184, Gly209, and His41. Further, MD simulation also identifies a notable H-bond interaction with Ser181 for all three hits. Among these hits, ZINC000143375720 shows the most stable binding interaction with TMPRSS2. The present study is successful in identifying TMPRSS2 ligands from zinc data base for a possible application in the treatment of COVID-19.


[Therapy of idiopathic oligozoospermia with bromicriptine. Results of a prospective controlled study].
The effect of bromocriptin on semen parameters and endocrine profiles in 25 males presenting idiopathic oligozoospermia was evaluated in a prospective controlled clinical trial versus 25 patients treated with placebo. Following results were obtained: a) Serum concentrations of prolactin decreased significantly during bromocriptin treatment while FSH, LH and Testosterone concentration remained unchanged. b) Sperm count, motility and morphology were not significantly affected by bromocriptin versus placebo. c) Conception rate was not significantly different between the treatment and placebo group. From the results of this study it can be concluded that bromocriptin is no suitable agent in the treatment of idiopathic, normoprolactinemic oligozoospermia.


Biomimetic ultrathin whitening by capillary-force-induced random clustering of hydrogel micropillar arrays.
Capillary-force-induced collapse of high-aspect-ratio microstructures has often been considered a failure mechanism in device fabrication. Here, we study capillary-force-induced clustering behavior of highly ordered hydrogel micropillar arrays from 2-hydroxyethyl methacrylate (HEMA) and methyl methacrylate (MMA) and explore their utility as ultrathin whitening layers (less than 9 mum thick). When exposed to water, followed by drying in an air stream, the micropillars were softened, bent, and randomly clustered together because of competition between the capillary force and elastic restoring force of the pillars. By varying the relative composition of the water-swellable PHEMA and glassy PMMA, we modulated the elastic modulus of the pillars in the wet state spanning over 3 orders of magnitude. By minimizing the sum of the capillary meniscus interaction energy and the elastic bending energy of the pillars for a cluster, we estimated the average cluster size as a function of the elastic modulus of the pillars, which agreed well with the experimental observation. The randomly clustered micropillar arrays appeared white in color because of random light scattering from the clusters, similar to the observation in the white beetles, whose scales consist of a few micrometer-thick random networks of microfilaments.


Scattering detection of a solenoidal Poynting vector field.
The Poynting vector S plays a central role in electrodynamics as it is directly related to the power and the momentum carried by an electromagnetic wave. In the presence of multiple electromagnetic waves with different polarizations and propagation directions, the Poynting vector may exhibit solenoidal components which are not associated to any power flow. Here, we demonstrate theoretically and experimentally that the presence of such solenoidal components has physical consequences, and it is not a mere artifact of the gauge invariance of S. In particular, we identify a simple field configuration displaying solenoidal components of S and theoretically show that a judiciously designed scatterer can act as a "Poynting vector detector" which when immersed in such field distribution would experience a transverse optical force orthogonal to the incidence plane. We experimentally validate our theoretical predictions by observing a pronounced asymmetry in the scattering pattern of a spherical nanoparticle.


Type 2 diabetes mellitus in childhood--a global perspective.
Type 2 diabetes mellitus is a group of diseases of different etiologies but similar symptopathology characterized by insulin resistance (insulin insensitivity) of different degrees. It can be associated with specific genetic mutations, with a series of chromosomal abnormalities, with states of lean body or obesity, the latter showing a worrying increase in incidence. The literature on the above is reviewed and a personal opinion is expressed on the prevention and treatment of the above conditions.


Association of body size and muscle strength with incidence of coronary heart disease and cerebrovascular diseases: a population-based cohort study of one million Swedish men.
Muscle strength and body size may be associated with coronary heart disease (CHD) and stroke risk. However, perhaps because of a low number of cases, existing evidence is inconsistent. Height, weight, systolic (SBP) and diastolic blood pressure (DBP), elbow flexion, hand grip and knee extension strength were measured in young adulthood in 1 145 467 Swedish men born between 1951 and 1976. Information on own and parental social position was derived from censuses. During the register-based follow-up until the end of 2006, 12 323 CHD and 8865 stroke cases emerged, including 1431 intracerebral haemorrhage, 1316 subarachoid haemorrhage and 2944 intracerebral infarction cases. Hazard ratios (HR) per 1 SD in the exposures of interest were computed using Cox proportional hazard model. Body mass index (BMI, kg/m(2)) showed increased risk with CHD and intracerebral infarction, whereas for intracerebral and subarachoid haemorrhage both under- and overweight was associated with increased risk. Height was inversely associated with CHD and all types of stroke. After adjustment for height, BMI, SBP, DBP and social position, all strength indicators were inversely associated with disease risk. For CHD and intracerebral infarction, grip strength showed the strongest association (HR = 0.89 and 0.91, respectively) whereas for intracerebral and subarachoid haemorrhage, knee extension strength was the best predictor (HR = 0.88 and 0.92, respectively). Body size and muscle strength in young adulthood are important predictors of risk of CHD and stroke in later life. In addition to adiposity, underweight needs attention since it may predispose to cerebrovascular complications.


UNC5B Promotes Vascular Endothelial Cell Senescence via the ROS-Mediated P53 Pathway.
Vascular endothelial cell senescence is involved in human aging and age-related vascular disorders. Guidance receptor UNC5B is implicated in oxidative stress and angiogenesis. Nonetheless, little is known about the role of UNC5B in endothelial cell senescence. Here, we cultured primary human umbilical vein endothelial cells to young and senescent phases. Subsequently, the expression of UNC5B was identified in replicative senescent cells, and then, its effect on endothelial cell senescence was confirmed by UNC5B-overexpressing lentiviral vectors and RNA interference. Overexpression of UNC5B in young endothelial cells significantly increased senescence-associated β-galactosidase-positive cells, upregulated the mRNAs expression of the senescence-associated secretory phenotype genes, reduced total cell number, and inhibited the potential for cell proliferation. Furthermore, overexpression of UNC5B promoted the generation of intracellular reactive oxygen species (ROS) and activated the P53 pathway. Besides, overexpression of UNC5B disturbed endothelial function by inhibiting cell migration and tube formation. Nevertheless, silencing UNC5B generated conflicting outcomes. Blocking ROS production or inhibiting the function of P53 rescued endothelial cell senescence induced by UNC5B. These findings suggest that UNC5B promotes endothelial cell senescence, potentially by activating the ROS-P53 pathway. Therefore, inhibiting UNC5B might reduce endothelial cell senescence and hinder age-related vascular disorders.


High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report.
Advanced glycation end products (AGEs) are important in the pathophysiology of type 2 diabetes mellitus (T2DM). They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL), carboxymethyllysine (CML), and methyl-glyoxal-hydro-imidazolone (MG-H1). Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.


Left ventricular structure and function by echocardiography in childhood swimmers.
The purpose of this study was to determine the differences in the left ventricular dimensions, mass index and function in school-aged swimmers by echocardiography. The study group consisted of 82 swimmers who participated in a systematic swimming training for at least six months, and the control group consisted of 41 sedentary children of similar age, sex and weight. In the study group, left ventricular dimensions and wall thicknesses, aortic root and left atrium diameters, and left ventricle mass index were significantly greater than the normal children (p < 0.05). However, there was no difference in the left ventricular systolic function (ejection fraction, shortening fraction) or in the left ventricular filling characteristics (p > 0.05). In conclusion, in childhood swimmers there was a significant increase in left ventricular dimensions, wall thicknesses and mass index, but no differences in the systolic function and filling characteristics of the left ventricle. Thus, information on endurance training participation is necessary to interpret quantitative echocardiographic data.


Circulating troponin and further left ventricular ejection fraction improvement in patients with previously recovered left ventricular ejection fraction.
The aim of this study is to determine factors associated with long-term recovery of left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF) and if further recovery also occurs in this group. Among 621 participants enrolled in the Alberta Heart Failure Etiology and Analysis Team (HEART) Study, 316 with Stage C HF underwent comprehensive imaging and biomarker testing at enrolment and at 1-year follow up. Using pre-enrolment data, HF with recovered EF (HFrecEF) was defined as an absolute improvement ≥5% in LVEF from the prior lowest LVEF value, with a final LVEF value > 35% at or prior to study baseline. Participants with all LVEF > 40% were included for comparison. Hospitalization-free survival to 5 years was performed. The median cohort age was 66 years, and time from diagnosis was 4 years; 82% were male patients. Of the 316 patients, 95 (30%) patients had HFrecEF and 56 (18%) patients pHFrEF. On multivariate analysis, only shorter duration of HF was predictive of HFrecEF status. Over 1 year, LVEF increased in the HFrecEF group 4.0% (0.15-7.90, P = 0.042) as compared with persistent HFrEF, who in turn demonstrated higher baseline serum high sensitivity Troponin-T with further increase at follow up 0.55(0.33-0.86, P = 0.011). No change in any parameter in the HFpEF/HFmrEF group at follow up was observed. Patients with HFrecEF demonstrate evidence of additional late improvement in LVEF and unchanged troponin levels, in contrast to those with persistent HFrEF, where LVEF does not improve and serum troponin rises over time. These data help to inform mechanisms relating to late LV remodelling.


Synthesis of TiO2-Cu2+/CuI Nanocomposites and Evaluation of Antifungal and Cytotoxic Activity.
Fungal infections have become a significant public health concern due to their increasing recurrence and harmful effects on plants, animals, and humans. Opportunistic pathogens (among others from the genera Candida and Aspergillus) can be present in indoor air, becoming a risk for people with suppressed immune systems. Engineered nanomaterials are novel alternatives to traditional antifungal therapy. In this work, copper(I) iodide (CuI) and a copper-doped titanium dioxide-copper(I) iodide (TiO2-Cu2+/CuI) composite nanomaterials (NMs)-were synthesized and tested as antifungal agents. The materials were synthesized using sol-gel (TiO2-Cu2+) and co-precipitation (CuI) techniques. The resulting colloids were evaluated as antifungal agents against Candida parapsilosis and Aspergillus niger strains. The NMs were characterized by XRD, HRTEM, AFM, and DLS to evaluate their physicochemical properties. The NMs present a high size dispersion and different geometrical shapes of agglomerates. The antifungal capacity of the NMs by the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) was below 15 µg/mL against Candida parapsilosis and below 600 µg/mL against Aspergillus niger for both NMs. Holotomography microscopy showed that the NMs could penetrate cell membranes causing cell death through its rupture and reactive oxygen species (ROS) production. Cytotoxicity tests showed that NMs could be safe to use at low concentrations. The synthesized nanomaterials could be potential antifungal agents for biomedical or environmental applications.


Sequencing and computational approaches to identification and characterization of microbial organisms.
The recent advances in sequencing technologies and computational approaches are propelling scientists ever closer towards complete understanding of human-microbial interactions. The powerful sequencing platforms are rapidly producing huge amounts of nucleotide sequence data which are compiled into huge databases. This sequence data can be retrieved, assembled, and analyzed for identification of microbial pathogens and diagnosis of diseases. In this article, we present a commentary on how the metagenomics incorporated with microarray and new sequencing techniques are helping microbial detection and characterization.


IMHOTEP: virtual reality framework for surgical applications.
The data which is available to surgeons before, during and after surgery is steadily increasing in quantity as well as diversity. When planning a patient's treatment, this large amount of information can be difficult to interpret. To aid in processing the information, new methods need to be found to present multimodal patient data, ideally combining textual, imagery, temporal and 3D data in a holistic and context-aware system. We present an open-source framework which allows handling of patient data in a virtual reality (VR) environment. By using VR technology, the workspace available to the surgeon is maximized and 3D patient data is rendered in stereo, which increases depth perception. The framework organizes the data into workspaces and contains tools which allow users to control, manipulate and enhance the data. Due to the framework's modular design, it can easily be adapted and extended for various clinical applications. The framework was evaluated by clinical personnel (77 participants). The majority of the group stated that a complex surgical situation is easier to comprehend by using the framework, and that it is very well suited for education. Furthermore, the application to various clinical scenarios-including the simulation of excitation propagation in the human atrium-demonstrated the framework's adaptability. As a feasibility study, the framework was used during the planning phase of the surgical removal of a large central carcinoma from a patient's liver. The clinical evaluation showed a large potential and high acceptance for the VR environment in a medical context. The various applications confirmed that the framework is easily extended and can be used in real-time simulation as well as for the manipulation of complex anatomical structures.


Colloidal aggregation causes inhibition of G protein-coupled receptors.
Colloidal aggregation is the dominant mechanism for artifactual inhibition of soluble proteins, and controls against it are now widely deployed. Conversely, investigating this mechanism for membrane-bound receptors has proven difficult. Here we investigate the activity of four well-characterized aggregators against three G protein-coupled receptors (GPCRs) recognizing peptide and protein ligands. Each of the aggregators was active at micromolar concentrations against the three GPCRs in cell-based assays. This activity could be attenuated by either centrifugation of the inhibitor stock solution or by addition of Tween-80 detergent. In the absence of agonist, the aggregators acted as inverse agonists, consistent with a direct receptor interaction. Meanwhile, several literature GPCR ligands that resemble aggregators themselves formed colloids, by both physical and enzymological tests. These observations suggest that some GPCRs may be artifactually antagonized by colloidal aggregates, an effect that merits the attention of investigators in this field.


Etiology of bladder dysfunction secondary to partial outlet obstruction. Calcium disregulation in bladder power generation and the ability to perform work.
Similar to all smooth muscle, contraction of urinary bladder smooth muscle depends upon a rise in intracellular free calcium, which results from both calcium influx from extracellular spaces and calcium release from intracellular stores (calcium-induced calcium release [CICR]). Recent studies from our laboratory demonstrate that one of the major dysfunctions induced by partial outlet obstruction is a marked reduction in the participation of CICR (from IP3-sensitive and IP3-insensitive sites on the sarcoplasmic reticulum [SR]) during stimulation by both field stimulation (neurotransmitter release) and by direct muscarinic stimulation (bethanechol). Experimentally, rabbit urinary bladder function can be evaluated using an isolated whole bladder model. The current study utilizes the isolated whole bladder model to compare the effects of partial outlet obstruction on the responses to field stimulation and bethanechol with the responses of normal bladders following inhibition of CICR with the combination of thapsigargin+ryanodine. The parameters measured include the magnitude of pressure generation, rate of pressure generation, time to maximal pressure generation, percent volume emptied, rate of emptying, power generation, and work performed (both total work and work per ml emptied). Partial outlet obstruction resulted in virtually identical alterations in the responses of the bladder to stimulation (field stimulation and bethanechol) to that of inhibition of CICR by thapsigargin+ryanodine. Thus, these studies provide strong support for our hypothesis that the contractile dysfunctions secondary to partial outlet obstruction are directly related to a marked inhibition of the CICR component of the response to both field stimulation and bethanechol.


The human preproinsulin gene: synthesis, cloning, gene modification, and expression studies.
A 355 base pair (bp) DNA sequence coding for human preproinsulin has been assembled by joining a synthetic DNA leader sequence coding for 24 preregion amino acids to the previously synthesized DNA duplex of 277 bp constituting the sequence of BCA chain. It was next cloned in M13 mp8 single-stranded bacteriophage and subjected to site-specific mutagenesis and phase shifting to allow its inducible expression under lac operator control. An affinity leader sequence of 25 bp has been added in an attempt to facilitate purification of the preproinsulin.


[Diagnosis of echinococcosis in the population of Slovakia].
Serologically diagnosed cases of echinococcosis in man occurring over the years 1970-1990 are reported. In the given period 292 serum samples were examined obtained from patients clinically suspected of echinococcosis, either with or without indication of localization in different organs. Of the total of 22 serologically positive patients echinococcal cysts were found in the liver in 17 patients (77.27%), in the lungs in three (13.63%) and in two patients the localization was not established. The patients with positive serological finding were within the age range of 33 to 68 years, with the exception of one 11-year-old boy. The value of serological examination of echinococcosis in the subjects involved in our study is highlighted by the findings in those patients who underwent surgery. Both the positive and the negative serological results were confirmed by the surgical findings of the presence or absence of echinococcus. (Tab. 3, Ref. 22.)


Radiologic and ultrasonographic diagnosis of gallstones.
Several new nonsurgical modes of therapy for gallstone disease are being introduced almost simultaneously in the United States. These include orally administered bile acids, contact dissolution with methyl t-butyl ether (MTBE), and extracorporeal shock wave lithotripsy. Paralleling these developments is a similar period of transition in the field of gallstone imaging. Technical considerations in performing ultrasonographic, roentgenographic, and cholecystographic studies become more important, since the criteria for use of the nonsurgical techniques place a greater emphasis on gallstone morphology. In ultrasonography, sizing artifacts from reflective surfaces, optimizing measurements, magnifying hard-copy images, positioning the patient, and optimizing transducer frequencies will need to be addressed. In roentgenography, coned views of the right upper quadrant, with the patient prone, will give the best results. Oral cholecystography (OCG) has largely been replaced by ultrasonography for the detection of gallstones, but it is still an essential part of the imaging workup because it permits adequate visualization of the gallbladder to assure patency of the cystic duct. Correlation of the findings from the several techniques has disclosed new insights and encouraged the use of tailored techniques. Based on the current criteria for the use of orally administered ursodeoxycholic acid, an estimated 60-70% of all patients who have gallstones may be suitable candidates for such treatment.


Management of Post-Traumatic Nightmares: a Review of Pharmacologic and Nonpharmacologic Treatments Since 2013.
Post-traumatic nightmares (PTN) are a common and enduring problem for individuals with post-traumatic stress disorder (PTSD) and other clinical presentations. PTN cause significant distress, are associated with large costs, and are an independent risk factor for suicide. Pharmacological and non-pharmacological treatment options for PTN exist. A previous review in this journal demonstrated that Prazosin, an alpha blocker, was a preferred pharmacological treatment for PTN and imagery rescripting therapy (IRT) was a preferred non-pharmacological treatment. Since that time, new and important research findings create the need for an updated review. Based on the results of a recent study in the New England Journal of Medicine, Prazosin has been downgraded by both the American Academy of Sleep Medicine (AASM) and the Veterans Health Administration/Department of Defense (VA/DoD) for PTN. In Canada, Nabilone, a synthetic cannabinoid, appears to be promising. Few recent studies have been published on non-pharmacological interventions for PTN; however, recent data is available with regard to using IRT on an inpatient setting, with German combat veterans, and through the use of virtual technology. Recent evidence supports the use of exposure, relaxation, and rescripting therapy (ERRT) with children and individuals with comorbid bipolar disorder and PTN. Prazosin is no longer considered a first-line pharmacological intervention for PTN by AASM and VA/DoD. However, in the absence of a suitable alternative, it will likely remain the preferred option of prescribers. IRT and ERRT remain preferred non-pharmacological treatments of PTN. Combining cognitive behavior therapy for insomnia (CBT-I) with IRT or ERRT may lead to improved outcomes.


A two-stage pretreatment approach to maximise sugar yield and enhance reactive lignin recovery from poplar wood chips.
A two-stage pretreatment approach, employing steam followed by organosolv treatment, was assessed for its ability to fractionate and recover most of the hemicellulose, lignin and cellulose components of poplar wood chips. A mild steaming stage was initially used to maximise hemicellulose sugar recovery, with 63% of the original xylan solubilised and recovered after this stage and close to 90% recovered in total. Rather than hindering subsequent organosolv delignification, the prior steam treatment enhanced lignin solubilisation with more than 66% of the original lignin removed after the two-stage pretreatment. The extracted lignin contained at least equal or greater amounts of functional groups as compared to the lignin solubilised after a single-stage organosolv pretreatment. More than 98% of the original cellulose was recovered after the two-stage pretreatment and 88% of the cellulose could be hydrolysed to glucose at enzyme loading of 5FPU/g cellulose after 72h.


Plasma RANKL level is not a reliable marker to monitor the bone destruction in mice model of osteomyelitis.
In this experimental study, we aimed to investigate the specific value of receptor activator of nuclear factor kappa-Β ligand (RANKL) plasma level in osteomyelitis to show the bone destruction and to determine its correlation with classical markers of infection in mice model of osteomyelitis. Sixty Balb/c female mice (30 to 40 g weight, 3.5 to 4 month-old) were divided into two groups: Controls (n=15) and study group (n=45). All mice underwent tibial decortication and received an injection of sclerosing agent into the intramedullary cavity. The next process was proceeded in two steps to observe the detectability of osteomyelitis-induced bone destruction (step 1) and treatment response (step 2) using the variables examined in our study. In step 1, the study group received 1 mL solution containing Staphylococcus aureus (S. aureus) bacteria (2X108 per mL) into the intramedullary cavity. Five mice from each group were sacrificed every seven days for three weeks and tibia and blood samples were obtained. In step 2, the remaining 30 infected mice were further divided into two groups to investigate the possible value of RANKL plasma level as a marker of treatment response. Fifteen of these mice received teicoplanin 20 mg/kg for four weeks, while the rest did not receive antibiotics. Eight mice from each group were sacrificed at the end of the second week and the remaining 14 mice were sacrificed at the end of four weeks. Complete blood count, procalcitonin level, C-reactive protein (CRP), and RANKL concentrations were measured from blood samples of each sacrificed mouse. Median RANKL concentration of the control subjects was significantly higher than recipients of intervention at the first and third weeks in step 1 where bone destruction of osteomyelitis was examined. No significant changes occurred in groups receiving and not receiving antimicrobial treatment in terms of RANKL, CRP, and procalcitonin levels throughout four weeks in step 2. The RANKL concentration was significantly correlated with colony growth in subjects allocated to the S. aureus inoculation group (r=-0.547, p=0.035). The RANKL levels in mice with S. aureus osteomyelitis are not correlated with colony growth or other markers of inflammation and not useful for monitoring the response to antimicrobial treatment during osteomyelitis.


Microdose Flare-up Gonadotropin-releasing Hormone (GnRH) Agonist Versus GnRH Antagonist Protocols in Poor Ovarian Responders Undergoing Intracytoplasmic Sperm Injection.
Microdose flare-up GnRH agonist and GnRH antagonist have become more popular in the management of poor ovarian responders (POR) in recent years; however, the optimal protocol for POR patients undergoing in vitro fertilization has still been a challenge. In this observational study design, two hundred forty four poor ovarian responders were retrospectively evaluated for their response to GnRH agonist protocol (group-1, n=135) or GnRH antagonist protocol (group-2, n=109). Clinical pregnancy rate was the primary end point and was compared between the groups. Student t-test, Mann Whitney U test and χ (2)-test were used to compare the groups. The p<0.05 was considered to show a statistically significant result. The mean total gonadotropin doses were 3814±891 IU in group 1 and 3539±877 IU in group 2 (p=0.02). The number of metaphase-II oocytes (3.6±2.4 vs. 2.8±1.9, p=0.005) and implantation rates (27.8% vs. 18.8%, p=0.04) in group 1 and group 2, respectively were significantly different. The fertilization rate in group 1 and group 2 was 73% vs. 68%, respectively (p=0.5) and clinical pregnancy rate was 19.8% vs. 14.4%, respectively (p=0.13). The GnRH agonist microdose flare-up protocol has favorable outcomes with respect to the number of oocytes retrieved and implantation rate; nevertheless, the clinical pregnancy rate was found to be similar in comparison to GnRH antagonist protocol in poor ovarian responders. GnRH antagonist protocol appears to be promising with significantly lower gonadotropin requirement and lower treatment cost in poor ovarian responders.


Study on spontaneous cerebrospinal fluid rhinorrhoea: its aetiology and management.
The aim of this study was to identify the common features in a study group of patients with spontaneous cerebrospinal fluid (CSF) rhinorrhoea, to develop a hypothesis to explain the cause of this condition and to investigate the outcome of surgical techniques adopted to repair the leak. In this retrospective study the authors have reviewed all the cases of spontaneous CSF leaks attending and receiving treatment from the otolaryngology department of Queen Elizabeth Hospital, Birmingham, from 1992 to 2002. Of 34 patients with CSF leaks, 15 were spontaneous in nature and formed the study group. Of these 15 patients, 14 were female; with ages ranging from 37 to 70 years and a median age of 50 years. All the female patients were overweight with a body mass index (BMI) >24.9 and, of these, nine were considered obese with a BMI >30. It was attempted to identify common factors in the study group and it was evident that female sex, obesity and age played a key role in this condition. The follow-up period ranged from two to 98 months. Thirteen patients were asymptomatic but two patients remained symptomatic, one of these despite repeated surgical intervention.


Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies.
Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-β, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.


Ethical and policy implications of hospitalist systems.
Hospitalist systems raise ethical and policy concerns regarding informing patients about the hospitalist system itself, communication between primary care physicians and hospitalists, continuity of care, and conflicts of interest. Patients may worry that hospitalist systems are intended to achieve cost savings and that the role of the primary care physician as coordinator of care may be undermined. These concerns may be particularly salient for certain subgroups of patients. Hospitalists and health-care organizations that set up hospitalist systems should take steps to reduce the foreseeable risks that discontinuity of care might cause. Practice standards should be set for communication between primary care physicians and hospitalists and for involvement of primary physicians in inpatient care under certain circumstances. By setting such standards and monitoring performance, hospitalist systems can improve the quality of care and reassure patients.


The morality and tax avoidance: A sentiment and position taking analysis.
This paper examines the moral and legal underpinnings of corporate tax avoidance. Cast in terms of a totemic symbol that brand tax avoidance as within the purview of the law, the paper invokes the attributional frames of the new sociology of morality to examine the position of both the moral advocates and the amoral critics of aggressive tax avoidance. The paper uses the United Kingdom as a jurisdiction where complex tax planning by tax advisors serves as a measure of protection for corporations who may have already conceived that they are paying too much tax. Data for the paper came from semi-structured interviews conducted with tax accountants, consultants, parliamentarians, and government officials. To supplement the interviews, data from the Parliamentary Commission on Banking Standards were collected and analyzed to provide useful insights. The findings reveal that through effective tax planning, companies can reduce the present values of future tax payments. Given the singular justification of their actions within the contours of the tax rules, the moral culpability of organized tax avoidance is minimized, with very little liability attached. Tax avoidance is a morally charged area that is slowly drifting away from conventional social norms of what is right or wrong. It is hard not to see those in charge of tax regulation not using the findings of this paper to provide a more nuanced understanding of the intractable problems associated with corporate tax avoidance and use it as a reference point for regulatory reforms.


Modulation effects within the mean-field theory of electrolyte solutions.
The consequences of source charge and surface modulation are studied within the framework of the Poisson-Boltzmann theory of electrolyte solutions. Through a consideration of various examples, it is found that inherent modulation can lead to both like-charge attraction and overcharging effects.


Rapid activation of nuclear factor κB by 17β-estradiol and selective estrogen receptor modulators: pathways mediating cellular protection.
17β-Estradiol (E2) treatment activates a set of protective response that has been found to protect cells from injury and more importantly to significantly abate the injuries associated with trauma-hemorrhage in vivo. Rapid NF-κB activation has been found to be an important signaling step in E2-mediated protection in cell culture, in vivo ischemia, and trauma-hemorrhage. In the current study, we investigated the signaling cascades linking E2 signaling with NF-κB activation and the protective response and compared them with the effects of two selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen. Two candidate pathways, mitogen-activated protein kinases and phosphatidylinositol-3-kinase (PI3K) were studied. Selective inhibitors were used to identify each pathway's contribution to NF-κB activation. Treatment of human coronary artery endothelial cells with E2 activated PI3K/Akt, p38, and JNK, all of which activated ERK1/2 followed by NF-κB activation. The combined activation of Akt, p38, and JNK was essential to activate NF-κB. The two SERMs activated PI3K and p38, which then phosphorylated ERK1/2 and activated NF-κB independent of the JNK pathway. Nuclear factor κB activation by these compounds protected cells from hypoxia/reoxygenation injury. However, E2, unlike either SERM, led to modest increases in apoptosis through the JNK pathway. Selective estrogen receptor modulator treatment led to increased expression of the protective proteins, Mn superoxide dismutase, and endothelial nitric oxide synthase, which was not seen with E2. These results provide new insight into the pathways activating NF-κB by E2 and SERMs and demonstrate that SERMs may have greater protective benefits than E2 in adult endothelial cells and potentially in vivo, as well.


Cobra-PLA provides higher oropharyngeal leak pressure than LMA-Classic and LMA-Unique: A meta-analysis with 22 studies.
Cobra Perilaryngeal Airway (Cobra-PLA) is a relatively new single-use supraglottic device employed during general anesthesia. This meta-analysis includes randomized controlled trials (RCTs) yielding extensive comparison results among Cobra-PLA, Laryngeal Mask Airway (LMA)-Classic, and LMA-Unique.Two authors performed searches in EMBASE, CENTRAL, PubMed, and ScienceDirect to identify RCTs that compared Cobra-PLA with LMA-Classic and with LMA-Unique in patients undergoing general anesthesia. Both random- and fixed-effects models were used. Begg's funnel plot was used to evaluate publication bias.Twenty-two RCTs with a total of 1845 patients were included. Cobra-PLA offered significantly higher oropharyngeal leak pressure than LMA-Classic [mean difference (MD) = 3.56 (1.56, 5.55), P = .0005] and LMA-Unique [MD = 4.44 (2.12, 6.76), P = .0002]. First-insertion success rate, ease of insertion, insertion time, and reported complications among Cobra-PLA, LMA-Classic, and LMA-Unique were similar.Compared with the commonly used LMA-Classic and LMA-Unique, Cobra-PLA provides superior airway sealing.


Calibration and validation of a carbon oxidation system and determination of the bicarbonate retention factor and the dietary phenylalanine requirement, in the presence of excess tyrosine, of adult, female, mixed-breed dogs,.
Carbon oxidation methods have been used as rapid and sensitive methods to determine whole-body AA requirements in multiple species. The objectives of the current studies were to validate complete CO recovery, determine the bicarbonate retention factor, and estimate the Phe requirement, in the presence of excess Tyr, in adult dogs using the direct oxidation technique. In this series of studies, 2 oxidation chambers were constructed and calibrated to ensure accurate collection of breath CO. First, 104.6 ± 7.1% CO was recovered from chambers and suggests that the chambers were appropriately designed for complete and efficient CO recovery. Second, we determined bicarbonate retention in 5 dogs using repeated oral dosing of a bicarbonate tracer (NaHCO) with small meals. At isotopic and physiological steady state, 102.5 ± 2.6% of the delivered NaHCO was recovered in breath. Third, the Phe requirement, when Tyr was supplied in excess, was determined by the rate of appearance of CO in the breath (CO). Dogs ( = 5) were fed test diets with different concentrations of Phe ranging from deficient to excessive for 2 d prior to conducting the tracer studies. The mean Phe requirement (when Tyr was supplied in excess) was 0.535% of diet (upper 95% confidence interval = 0.645% diet) on an as-fed basis or 0.575% of diet (upper 95% confidence interval = 0.694% of diet) on a DM basis and was based on a calculated (modified Atwater calculation) dietary ME density of 3.73 Mcal/kg DM. These data support the use of carbon oxidation methods and oral dosing of isotope to measure whole-body requirements of indispensable AA in adult dogs and suggest the current recommendations may be low.


Detection and prevalence of antimicrobial resistance genes in Campylobacter spp. isolated from chickens and humans.
Campylobacter spp. are common pathogenic bacteria in both veterinary and human medicine. Infections caused by Campylobacter spp. are usually treated using antibiotics. However, the injudicious use of antibiotics has been proven to spearhead the emergence of antibiotic resistance. The purpose of this study was to detect the prevalence of antibiotic resistance genes in Campylobacter spp. isolated from chickens and human clinical cases in South Africa. One hundred and sixty one isolates of Campylobacter jejuni and Campylobacter coli were collected from chickens and human clinical cases and then screened for the presence of antimicrobial resistance genes. We observed a wide distribution of the tetO gene, which confers resistance to tetracycline. The gyrA genes that are responsible quinolone resistance were also detected. Finally, our study also detected the presence of the blaOXA-61, which is associated with ampicillin resistance. There was a higher (p < 0.05) prevalence of the studied antimicrobial resistance genes in chicken faeces compared with human clinical isolates. The tetO gene was the most prevalent gene detected, which was isolated at 64% and 68% from human and chicken isolates, respectively. The presence of gyrA genes was significantly (p < 0.05) associated with quinolone resistance. In conclusion, this study demonstrated the presence of gyrA (235 bp), gyrA (270 bp), blaOXA-61 and tetO antimicrobial resistance genes in C. jejuni and C. coli isolated from chickens and human clinical cases. This indicates that Campylobacter spp. have the potential of resistance to a number of antibiotic classes.


Defining tumor-associated vascular heterogeneity in pediatric high-grade and diffuse midline gliomas.
The blood-brain barrier (BBB) plays important roles in brain tumor pathogenesis and treatment response, yet our understanding of its function and heterogeneity within or across brain tumor types remains poorly characterized. Here we analyze the neurovascular unit (NVU) of pediatric high-grade glioma (pHGG) and diffuse midline glioma (DMG) using patient derived xenografts and natively forming glioma mouse models. We show tumor-associated vascular differences between these glioma subtypes, and parallels between PDX and mouse model systems, with DMG models maintaining a more normal vascular architecture, BBB function and endothelial transcriptional program relative to pHGG models. Unlike prior work in angiogenic brain tumors, we find that expression of secreted Wnt antagonists do not alter the tumor-associated vascular phenotype in DMG tumor models. Together, these findings highlight vascular heterogeneity between pHGG and DMG and differences in their response to alterations in developmental BBB signals that may participate in driving these pathological differences.


Systematic review of published trials: long-term safety of topical corticosteroids and topical calcineurin inhibitors in pediatric patients with atopic dermatitis.
Many clinicians have concerns about the safety of atopic dermatitis (AD) treatments, particularly in children requiring long-term daily maintenance therapy. Topical corticosteroids (TCS) have been widely used for >5 decades. Long-term TCS monotherapy has been associated with adverse cutaneous effects including atrophy, rebound flares, and increased percutaneous absorption with potential for adverse systemic effects. Topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, available for 1-2 decades, are not associated with atrophy or increased percutaneous absorption after prolonged use and have much lower potential for systemic effects. However, since 2006 TCIs have carried a controversial Boxed Warning based on a theoretical risk of malignancy (eg, skin and lymphoma) that has limited TCI use for standard-of-care maintenance therapy. A comparative systematic search of PubMed was done for long-term (≥12 week) clinical trials of TCS or TCI treatment in patients <12 years with AD. Citations were reviewed for inclusion based on MeSH terms, abstracts, and relevant article text. Studies were excluded if they did not encompass subjects <12 years, or were <12 weeks' duration, retrospective, meta-analyses, or limited to anecdotal case reports. Of 27 trials meeting criteria, 21 included 5825 pediatric patients treated with TCIs, and 6 included 1999 patients treated with TCS. TCS studies were limited to low- to mid-potency products, and all but one study lacked a vehicle control. Eight TCI studies were vehicle-controlled, and safety data were well reported, with ≤5 % of patients reporting discontinuation due to adverse effects (DAEs). Cutaneous and systemic adverse events (AEs) were similar in TCI and vehicle groups, with no reports of lymphoma. Safety data in TCS trials were less well reported. DAE incidence was addressed in just 2 trials, and systemic and cutaneous AEs were mostly unreported. Data supporting long-term use of TCIs are robust, documenting safety and efficacy, while data supporting long-term TCS use are limited to low- to mid-potency products. Our review identifies a lack of information on the safety of commonly prescribed, long-term monotherapy with mid- to high-potency TCS in pediatric AD, and supports standard-of-care maintenance therapy with TCIs and intermittent use of low- to mid-potency TCS for flares.


Case report: Alagille syndrome.
The clinical case of a boy aged 6 years suffering from Alagille syndrome is described. This is a rare genetic disease characterised, from the hepatic point of view, by anomalies of the intrahepatic biliary ducts (in terms of number, histology and immunohistochemistry) with cholestasis; from the systemic point of view it is characterised by anomalies of various systems (heart, musculoskeletal system, eyes, face, kidneys and nervous system). The patient was referred for dental consultation by the Pediatric Cardiology Section, Sant'Orsola-Malpighi Polyclinic, Bologna City Hospital. Medical history indicated liver transplantation at 3 years; immunosuppressive treatment; heart disease with low risk of bacterial endocarditis (interventricular defect and systolic murmur). Objective examination revealed a dental formula compatible with his age, of a decided green colour (above all the permanent dentition) with numerous caries lesions on the posterior deciduous teeth. In agreeing the treatment plan with the cardiologist (treatment of caries and sealing the fissures and cracks in the permanent first molars) it was decided that antibiotic prophylaxis was not required since such conservative treatment is not at risk for bacterial endocarditis. The patient returned 15 min after the end of the second session with marked swelling of the right upper hemi-lip. Having excluded traumatic origin, a hypothesis was formulated of hypersensitivity to products used during the dental session, in particular talcum-coated gloves and latex rubber dam. The patient was referred immediately to the Dermatology Service, Sant'Orsola-Malpighi Polyclinic, for the appropriate dermatological tests (prick test and epicutaneous test) which confirmed the suspected diagnosis: urticaria from contact with latex materials. The clinical case described confirms the need for the dentist of an interdisciplinary approach in patients suffering from systemic diseases and/or syndromes.


A pilot project to design, implement and evaluate an electronic integrated care pathway.
The project focused on the design, implementation and evaluation of an electronic integrated care pathway (eICP), within a Mother and Baby Unit. Health care professionals and service users (stakeholders) were involved in the process in order to promote patient centred, co-constructed care. Questionnaire and discussion groups were used for data collection regarding the initial eICP development. Of 15 participants who took part in the design and development of the eICP, seven were able to take part in the evaluation process on the Unit. Results show that 100% (n = 7) of the participants were in agreement with the eICP and the format that was produced and implemented for trial on the Unit. Increased ownership of records, greater multi disciplinary involvement and enhanced patient experience were also reported. Recommendations for clinical practice include resource management, ownership of the research group, holism maintenance and the acquisition of computer skills.


Fix my child: The importance of including siblings in clinical assessments.
This study examined concordance in the attachment strategies of school-aged siblings with reference to environmental risk in terms of poverty and maltreatment. It also investigated the effect of child maltreatment and maternal mental illness on children's psychosocial functioning in terms of the Dynamic-Maturational Model of Attachment and Adaptation (DMM) including unresolved trauma and the DMM Depressed modifier. The attachment strategies of 30 sibling pairs, aged 5-14 years, were assessed using the School-age Assessment of Attachment (SAA). Unlike most previous studies, this study included siblings from large families of two to six children. The main finding was that as environmental risk increases, the diversity of sibling attachment strategies decreases with greater recourse to the DMM Type A3-6 and A/C strategies. Unlike previous studies, the highest level of concordance was found in sibling pairs with the opposite gender. Boys whose mothers had a history of mental illness were significantly more likely than girls to be assessed with the DMM-depression modifier. As danger increases, children in the same family experience more of the same childhood. Further research should focus on single case, intra-familial studies to build a systemic model of the shared environment. Research should also evaluate the effects of environmental risk compared with size of the sibling group on children's attachment strategies. The clinical implications point to the importance of assessing all children in the family using a model built around functional formulation rather than diagnosing the symptoms of a particular child.


The role of exposure to self-injury among peers in predicting later self-injury.
While researchers are beginning to reach consensus around key psychological correlates of non-suicidal self-injury (NSSI), comparatively less work has been done investigating the role and influence of peers. Given evidence that engagement in this behavior may be susceptible to peer influence, especially during the early stages of its course, the current study prospectively explored whether knowing a friend who self-injures is associated with the onset, severity, and subsequent engagement in NSSI. The moderating roles of adverse life events, substance use and previous suicidal behavior in this relationship also were explored. Self-report data were collected from 1,973 school-based adolescents (aged 12-18 years; 72 % female) at two time points, 1 year apart. Knowing a friend who self-injured, negative life events, psychological distress and thoughts of NSSI differentiated those who self-injured from those who did not, and also predicted the onset of NSSI within the study period. Further, adverse life events and previous thoughts of NSSI moderated the relationship between exposure to NSSI in peers and engaging in NSSI at Time 2. However, the effect of having a friend who self-injures was not related to the severity of NSSI. Having a friend who self-injures appears to be a risk factor for self-injury among youth who are experiencing high levels of distress. Implications of these findings are discussed.


The Effects of miR-136-5p-Mediated Regulation of A20 in Astrocytes from Cultured Spinal Cord Cultured Cells In Vitro.
This study focused on investigating the regulatory mechanism of miR-136-5p in mouse astrocytes stimulated with interleukin-17(IL-17). C57BL/6 mouse astrocytes were stimulated with IL-17 (100ng/ml) for various periods of time (0-48 hours) and at various doses (0-200 ng), and the expression levels of inflammatory cytokine and chemokine genes (IL-6, TNF-α, MCP-1, MCP-5 and MIP-2) were then detected by real-time PCR. The expression of the A20 gene was measured with real-time PCR in cells that were stimulated with IL-17 (50 ng/ml) for various periods of time (0-48 hours). C57BL/6 mouse astrocytes were transfected with Ctrl-anti-miR-136-5p or LNA -anti-miR-136-5p for 48 h. Thereafter, the cells were stimulated with or without IL-17 (50ng/ml) for 6 h. The level of A20 protein (TNFα-induced protein 3, TNFAIP3) was detected by Western blot analysis. (1) Compared with the DMEM control group, within six hours, IL-17 stimulation significantly increased the expression levels of inflammatory cytokine and chemokine genes and clearly decreased the expression level of the A20 protein. (2) Without IL-17 stimulation, the expression level of the miR-136-5p gene was significantly decreased, whereas in the miR-136-5p-inhibition group, the A20 protein expression was elevated. IL-17 stimulation slightly decreased the expression of the A20 protein in the miR-136-5p-inhibition group, but it was still slightly higher than in the control group. This study demonstrated that miR-136-5p affected the expression of A20 in IL-17-stimulated astrocytes.


Bio-analytical and chemical characterisation of offshore produced water effluents for estrogen receptor (ER) agonists.
The in vitro estrogen receptor (ER) agonist potency and C1 to C9 alkyl substituted phenol content of offshore produced water effluents collected from the UK sector of the North Sea were determined using a combination of bio-analytical and chemical analysis techniques. An in vitro reporter gene assay was used to determine ER agonist potency, whilst gas chromatography coupled to mass spectrometry (GC-MS) was used to quantify the concentration of alkylphenols. The in vitro ER agonist potency was highly variable and ranged from less than the limit of detection (theoretically 0.03 ng 17beta-estradiol (E2) l(-1)) to 91 ng E2 l(-1). C1 to C5 alkylphenol concentrations were also highly variable ranging from 5 to 1600 microg l(-1) with a median concentration of 206 microg l(-1). These data reflect the highly variable composition of produced water discharges from different fields. The observed poor correlation of the alkylphenol isomer content and ER agonist activity suggests that other compounds present in the produced water discharges may be responsible for the ER agonist activity observed. It is recommended that further work be performed to characterise the full range of ER agonists present in offshore produced water discharges.


Formation of Transient Protein Aggregate-like Centers Is a General Strategy Postponing Degradation of Misfolded Intermediates.
When misfolded intermediates accumulate during heat shock, the protein quality control system promotes cellular adaptation strategies. In Schizosaccharomyces pombe, thermo-sensitive proteins assemble upon stress into protein aggregate-like centers, PACs, to escape from degradation. The role of this protein deposition strategy has been elusive due to the use of different model systems and reporters, and to the addition of artificial inhibitors, which made interpretation of the results difficult. Here, we compare fission and budding yeast model systems, expressing the same misfolding reporters in experiments lacking proteasome or translation inhibitors. We demonstrate that mild heat shock triggers reversible PAC formation, with the collapse of both reporters and chaperones in a process largely mediated by chaperones. This assembly postpones proteasomal degradation of the misfolding reporters, and their Hsp104-dependent disassembly occurs during stress recovery. Severe heat shock induces formation of cytosolic PACs, but also of nuclear structures resembling nucleolar rings, NuRs, presumably to halt nuclear functions. Our study demonstrates that these distantly related yeasts use very similar strategies to adapt and survive to mild and severe heat shock and that aggregate-like formation is a general cellular scheme to postpone protein degradation and facilitate exit from stress.


Influence of wheat bran and of a bulk-forming ispaghula cathartic on the bioavailability of digoxin in geriatric in-patients.
The present randomized study compared the influence of a gel-forming wheat bran with a nongel-forming bulk cathartic (an ispaghula formulation, Vi-Siblin S) on the steady state concentrations of digoxin in plasma in 30 geriatric in-patients treated with either combination (16 with wheat bran + digoxin, 14 with ispaghula + digoxin) for 4 weeks. After 2 but not after 4 weeks, wheat bran reduced the digoxin levels, although the levels were still within the therapeutic range. Ispaghula had no influence at any time. It is concluded that neither wheat bran nor the ispaghula formulation has any clinically relevant influence on therapeutic digoxin levels in geriatric patients.


MKRN1/2 serve as tumor suppressors in renal clear cell carcinoma by regulating the expression of p53.
Kidney renal clear cell carcinoma (KIRC) belongs to renal cell carcinoma which is a very aggressive malignant tumor with poor prognosis and high mortality. The MKRN family includes three members MKRN1, MKRN2 and MKRN3, which are closely related to cancers, and have been involved in many studies. This study aimed to explore the roles of MKRN family in KIRC. The expression of MKRNs was analyzed using the UALCAN database, prognostic analysis was performed with the GEPIA2 and Kaplan-Meier Plotter database, and correlation analysis was assessed by GEPIA2. The CCK-8 and colony formation assay were performed to detect cell proliferation, wound healing assays were performed to detect cell migration, cell cycles were detected by flow cytometry analysis, GST pull-down and co-immunoprecipitation assays were performed to detect the interaction of proteins, and the expression of MKRNs, p53 and other proteins were detect by immunoblotting analysis or quantitative PCR (qPCR). MKRN1 and MKRN2 were lowly expressed in KIRC samples compared to the corresponding normal tissues, and KIRC patients with high levels of MKRN1 and MKRN2 showed higher overall survival (OS) and disease free survival (DFS) rates. The overexpression of MKRN1 and MKRN2 inhibited the proliferation of human KIRC cells by arresting the cell cycles, but shows little effect on cells migration. The expression of MKRN1 and MKRN2 are correlated, and MKRN1 directly interacts with MKRN2. Moreover, both MKRN1 and MKRN2 were closely correlated with the expression of TP53 in KIRC tumor, and promoted the expression of p53 both at protein and mRNA levels. Our study suggests that MKRN1 and MKRN2 serve as tumor suppressors in KIRC, and act as promising therapeutic targets for KIRC treatment.


CIRCADIAN PERIODICITY IN THE CONCENTRATION OF PROLACTIN IN THE RAT HYPOPHYSIS.
Prolactin activity in the hypophyses of rats maintained under standardized conditions was assayed in pigeons. The concentration of prolactin in the gland exhibited a circadian rhythm.


Comparison of radiance and polarization values observed in the Mediterranean Sea and simulated in a Monte Carlo model.
Measurements of the radiance and degree of polarization made in 1971 in the Mediterranean Sea are presented along with the simulation of all observed quantities by a Monte Carlo technique. It is shown that our independent scattering treatment utilizing a Stokes vector formalism to describe the polarization state of the light field produces remarkably good agreement with those values measured in situ.


Anatomist on the dissecting table? Dutch anatomical professionals' views on body donation.
Anatomical professionals know better than anyone else that donated bodies are a valuable asset to anatomical science and medical education. They highly value voluntary donations, since a dearth of bodies negatively affects their profession. With this in mind, we conducted a survey (n = 54) at the 171st scientific meeting of the Dutch Anatomical Society in 2009 to see to what extent anatomical professionals are willing to donate their own body. The results reveal that none of the survey participants are registered as a whole body donor and that only a quarter of them would consider the possibility of body donation. We argue that the two main constraints preventing Dutch anatomical professionals from donating their own body are their professional and their social environments. In contrast to the absence of registered body donors, half of the anatomical professionals are registered as an organ donor. This figure far exceeds the proportion of registered organ donors among the general Dutch population.


The Value of PDRI and P-PASS as Predictors of Outcome After Pancreas Transplantation in a Large European Pancreas Transplantation Center.
In 2008, the preprocurement pancreas suitability score (P-PASS) was introduced within Eurotransplant to predict suitability of pancreas donors. A P-PASS of 17 or higher would have lower graft survival compared with pancreatic grafts from donors with a P-PASS lower than 17. In 2010, a continuous model, the pancreas donor risk index (PDRI), was designed. Before using this model in the European donor population, it has to be validated in the European setting. In this study, P-PASS and PDRI were validated using the results of all pancreas transplants performed at our center. The P-PASS and PDRI were compared as both continuous and dichotomous values. The original cutoff point of 17 divided P-PASS groups. Median PDRI (1.24) divided PDRI groups. In total, 349 pancreas transplantations were performed. The P-PASS of 17 or higher was not associated with graft survival (P = 0.448). The PDRI of 1.24 or higher was associated with reduced graft survival in univariate analysis (P = 0.007) and multivariate analysis (P = 0.002). The PDRI concordance index was 0.69. The P-PASS has no predictive value for pancreas graft survival and should not be used in clinical decision making. The PDRI is a significant predictor of pancreas graft survival but should be used carefully, because good results can be achieved with grafts from high-PDRI donors.


Physical and psychological nicotine dependence in Greeks: an epidemiological study.
Smoking is the most widespread addictive behaviour in the world, as it causes physical and psychological dependence on nicotine. The objective of the present study was to discern the prevalence and the relative risks of nicotine dependence of adult people in Athens, Greece, as this country holds first place in cigarette consumption in the European Union. A random sample of 202 current smokers (82 men and 120 women) was drawn from residents aged v 18 years in Athens, the capital of Greece. A questionnaire on the physical (Fagerstrom Test of Nicotine Dependence) and psychological (American Psychiatric Association's diagnostic criteria of nicotine abuse) nicotine dependence was used. According to the results of the present study, 12.4% of the sample reported null physical nicotine dependence, and 31.7% had low, 25.7% had moderate and 30.2% had high nicotine dependence. Multiple logistic regression analysis revealed that younger people (aged 18 to 24 and 25 to 34, odds ratio [OR] = 0.047, P < or = 0.033 and OR = 0.096, P < or = 0.038, respectively) were less prone to developing physical dependence. Women tended to be systematically less dependent than men (25% and 37.8% high dependence, respectively). Furthermore, 75.7% of the sample had psychological nicotine dependence. Binary logistic regression analysis and chi-square test revealed that younger people (18- to 24-year-olds, OR = 0.081, P < or = 0.008) and individuals of inferior education (v2 = 7.826, P < or = 0.05) were less prone to develop psychological dependence. In addition, women showed a higher percentage of withdrawal symptoms compared with men (80% and 68%, respectively). The results of the present study provided compelling evidence that physical and, in particular, psychological nicotine dependence of adult people in Athens, Greece, was significant, and this calls for a course of action that should be taken by public health policy-makers to reduce smoke consumption.


The effect of mouthrinse containing calcium glycerophosphate on the chemical composition and development of plaque in humans.
Children rinsed twice daily with one of two concentrations of calcium glycerophosphate or a placebo. Plaque was collected at two-week intervals for eight weeks, and Löe and Silness Indices determined. Results indicate a lower index rating and a higher phosphorus content for experimental groups than for the control at the four-week examination.


An assessment of approximating aspheres with more easily manufactured surfaces.
In designing optical systems for synchrotron radiation, one is often led to conclude that optimal performance can be obtained from optical surfaces described by conic sections of revolution, usually paraboloids and ellipsoids. The resulting design can lead to prescriptions for three-dimensional optical surfaces that are difficult to fabricate accurately. Under some circumstances satisfactory system performance can be achieved through the use of more easily manufactured surfaces such as cylinders, cones, bent cones, toroids and elliptical cylinders. These surfaces often have the additional benefits of scalability to large aperture, lower surface roughness and improved surface figure accuracy. In this paper we explore some of the conditions under which these more easily manufactured surfaces can be utilized without sacrificing performance.


Brain Structures and Networks Underlying Treatment Response to Deep Brain Stimulation Targeting the Inferior Thalamic Peduncle in Obsessive-Compulsive Disorder.
Obsessive-compulsive disorder (OCD) is a debilitating disease with a lifetime prevalence of 2-3%. Neuromodulatory treatments have been successfully used in severe cases. Deep brain stimulation (DBS) targeting the inferior thalamic peduncle (ITP) has been shown to successfully alleviate symptoms in OCD patients; however, the brain circuits implicated remain unclear. Here, we investigate the efficacious neural substrates following ITP-DBS for OCD. High-quality normative structural and functional connectomics and voxel-wise probabilistic mapping techniques were applied to assess the neural substrates of OCD symptom alleviation in a cohort of 5 ITP-DBS patients. The region of most efficacious stimulation was located in the regions of the ITP and bed nucleus of the stria terminalis. Both functional and structural connectomics analyses demonstrated that successful symptom alleviation involved a brain network encompassing the bilateral amygdala and prefrontal regions. The main limitation is the small size of the ITP-DBS cohort. While the findings are highly consistent and significant, these should be validated in larger studies. These results identify a tripartite brain network - composed of the bilateral amygdala and prefrontal regions 24 and 46 - whose engagement is associated with greater symptom improvement. They also provide information for optimizing targeting and identifying network components critically involved in ITP-DBS treatment response. Amygdala engagement in particular seems to be a key component for clinical benefits and could constitute a biomarker for treatment optimization.


Family history of acute appendicitis.
To evaluate the association of acute appendicitis with age, sex, Alvarado score (AS) and family history. Medical records of 2670 patients, who were admitted to our hospital's emergency department between January 2005 and June 2007, were reviewed. These patients were referred as acute abdominal pain by general practitioners. The data of patients were devided into sub-groups according to their age, sex, operative status, AS status and having a pathologically confirmed postoperative diagnose of acute appendicitis or not. Logistic regression analysis was performed to find out relationships among the sub-groups. Male gender (1.37), age < 50 (2.4), positive family history (3.16), AS 5-6 (13) and AS 7 (31) increased the risk of acute appendicitis. The sensitivity and specificity of AS was 91.5% and 60.5% respectively. The sensitivity and specificity of family history was 68.9% and 75.4% respectively. Family history is an important parameter while predicting acute appendicitis.


Importance of the intellectual property system in attempting compulsory licensing of pharmaceuticals: a cross-sectional analysis.
Recently, interest in compulsory licensing of pharmaceuticals has been growing regardless of a country's income- level. We aim to investigate the use of compulsory licensing as a legitimate part of the patent system and tool for the government to utilize by demonstrating that countries with a mature patent system were more likely to utilize compulsory licensing of pharmaceuticals. We used a multivariate logistic model to regress attempts to issue compulsory licensing on the characteristics of the intellectual property system, controlling for macro context variables and other explanatory variables at a country level. A total 139 countries, selected from members of the World Trade Organization, were divided into a CL-attempted group (N = 24) and a non-CL-attempted group (N = 115). An attempt to issue compulsory licensing was associated with population (+) and a dummy variable for other regions, including Europe and North America (-). After controlling for macro context variables, mature intellectual property system was positively associated with attempting compulsory licensing. Our study provided evidence of an association between attempting compulsory licensing and matured patent systems. This finding contradicts our current understanding of compulsory licensing, such as compulsory licensing as a measure to usurp traditional patent systems and sometimes diametrically opposed to the patent system. The findings also suggest a new role of compulsory licensing in current patent systems: compulsory licensing could be a potential alternative or complement to achieve access to medicines in health systems through manufacturing and exporting patented pharmaceuticals.


Evaluation of the Antidiarrheal Activity of Hydromethanol Crude Extracts of Ruta chalepensis and Vernonia amygdalina in Mice.
The herbal medicine practitioners in Ethiopia have used a wide range of medicinal plants as antidiarrheal agents. Among these, Ruta chalepensis and Vernonia amygdalina were claimed to have antidiarrheal activity in Ethiopian folklore medicine. Hence, the aim of the present study was to evaluate the antidiarrheal activity of the crude extracts of Ruta chalepensis and Vernonia amygdalina in mice. The crude extracts were obtained by cold maceration with 80% methanol, and its antidiarrheal activities were evaluated using a castor oil-induced diarrheal model. The test groups were treated with 100, 200, and 400 mg/kg body weight (bw) of the crude extract of each plant, while the positive controls and negative controls were given loperamide (3 mg/kg.bw) and 2% Tween 80 (10 ml/kg.bw), respectively. In the castor oil-induced model, the crude extract of Ruta chalepensis (200 and 400 mg/kg.bw) significantly prolonged the onset of diarrhea in mice. Besides, it also showed a significant reduction in the frequency of stooling and weight of feces. Contrastingly, the crude extract of Vernonia amygdalina had a significant effect in delaying the onset of time of diarrhea and reduction of the frequency of stool and the weight of feces only at the maximum tested dose (400 mg/kg.bw). The present study demonstrated that the crude leaves extract of Ruta chalepensis (200 and 400 mg/kg.bw) and Vernonia amygdalina (400 mg/kg.bw) possessed significant antidiarrheal activity in the castor oil-induced diarrheal model.


The relevance of carbohydrate hydrogen-bonding cooperativity effects: a cooperative 1,2-trans-diaxial diol and amido alcohol hydrogen-bonding array as an efficient carbohydrate-phosphate binding motif in nonpolar media.
Carbohydrates with suitably positioned intramolecularly hydrogen-bonded hydroxyl and amide groups have the potential to act as efficient bidentate phosphate binders by taking advantage of sigma- and/or ,sigma,pi-H-bonding cooperativity in nonpolar solvents. Donor-donor 1,2-trans-diaxial amido alcohol (1) and diol (3), in which one of the donor centres is cooperative, are very efficient carbohydrate-phosphate binding motifs. We have proven and quantified the key role of hydrogen-bonding centres indirectly involved in complexation, which serve to generate an intramolecular H-bond (six-membered cis H-bond) in 1 and 3. This motif enhances the donor nature of the H-bonding centres that are directly involved in complexation. A comparison of the thermodynamic parameters of the complexes formed between phosphate and a cooperative (1-Phos) or anti-cooperative (2-Phos) bidentate H-bonded motif of a carbohydrate has allowed us to quantify the energetic advantage of H-bonding cooperativity in CDCl3 and CDCl3/CCl4 (1:1.3) (Delta Delta G degrees=-2.2 and -2.0 kcal mol(-1), respectively). The solvent dependences of the entropy and enthalpy contributions to binding provide a valuable example of the delicate balance between entropy and enthalpy that can arise for a single process, providing effective cooperative binding in terms of Delta G degrees.


Recent updates on acetaminophen hepatotoxicity: the role of nrf2 in hepatoprotection.
Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.


Prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy.
Although traditionally associated with polycythemia, COPD has a systemic inflammatory component that could interfere with erythropoiesis. This study describes the distribution and prognostic value of the hematocrit in patients with severe COPD receiving long-term oxygen therapy (LTOT). A total of 2,524 patients with COPD, FEV1/vital capacity (VC) < 70%, FEV1 < 80% of predicted, and Pa(O2) < 7.3 kPa in whom a hematocrit was available at entry was identified between 1980 and 1999 in the French Association Nationale pour le Traitement à Domicile de l'Insuffisance Respiratoire chronic respiratory insufficiency and home-care database (male/female ratio, 5/1; mean +/- SD age, 68 +/- 10 years for men, and 70 +/- 10 years for women). Correlations between hematocrit, demographic data, and pulmonary function data were examined. A multivariate Cox proportional hazard regression was performed to identify prognostic factors. Mean hematocrit was 45.9 +/- 7.0% in men and 43.9 +/- 6.0% in women (< 39% in 12.6% of men, and < 36% in 8.2% of women) according to the World Health Organization definition of anemia. Hematocrit was negatively correlated with age (r = - 0.245) and FEV1/VC (r = - 0.068) and was positively correlated with Pa(CO2) (r = 0.161) and body mass index (r = 0.127). Multivariate analysis found hematocrit to be an independent predictor of survival, hospital admission rate, and cumulative duration of hospitalization. The 3-year survival was 24% (95% confidence interval, 16 to 33%) when the hematocrit was < 35%, and 70% (63 to 76%) when the hematocrit was > or = 55%. A low hematocrit is not uncommon in LTOT/COPD patients. Hematocrit is negatively associated with mortality and morbidity. Whether the association is causative or not and whether or not corrective measures are warranted remain to be determined.


Factors Associated with Number of Present Teeth in Adults in Japanese Urban City.
The purpose of this study was to identify which factors were associated with number of present teeth (PT) in older adults as their clarification might contribute to maintaining the number of PT in this population. These factors were investigated by means of a questionnaire on oral health condition, general health behavior, and anamnesis of diabetes mellitus together with a dental examination. Data were obtained from a total of 7,741 Japanese subjects (2,623 males and 5,118 females), all of whom were aged 40, 50, or 60 years. Significant differences were observed in the mean number of PT between a positive or negative response to questions on anamnesis of diabetes mellitus, current smoking, and having loose teeth in all age groups in males; significant differences were also observed for current smoking, lower intake of dairy milk products, having loose teeth, no experience of tooth brushing instruction, and poor oral hygiene status in all age groups in females. Stepwise logistic regression analysis revealed having loose teeth (odds ratio [OR], 1.82), gingival swelling (OR, 1.40), an anamnesis of diabetes mellitus (OR, 1.72), current smoking (OR, 1.86), lower intake of dairy milk products (OR, 1.22), preference for salty seasonings (OR, 1.23), frequent sweet intake (OR, 1.29), no experience of tooth brushing instruction (OR, 1.38), and poor oral hygiene (OR, 2.04) as significant risk factors for the number of PT being <24 after adjusting for age and sex. These results indicate that an anamnesis of diabetes mellitus, a history of smoking, the presence of loose teeth, and poor oral hygiene status in a self-reported evaluation of oral health might correlate with <24 PT in older adults.


The association between homocysteine (hcy) and serum natural antioxidants in elderly bone mineral densitometry (BMD).
Previous studies showed oxidative stress had an important impact on osteoclastic and osteoblastic functions. Oxidative stress or low levels of antioxidants are supposed to reduce BMD and cause osteoporosis. hcy, gamma glutamyltransferase (GGT), uric acid, albumin and total bilirubin are simple laboratory parameters that are related with oxidative stress. In this study we compare the serum hcy and antioxidant levels in patients with osteoporosis, osteopenia and control subjects. A total of 2190 elderly persons (1348 patients with osteoporosis, 643 patients with osteopenia and 199 control subjects) who were referred to the outpatient clinic of the Department of Internal Medicine, Division of Geriatric Medicine at Hacettepe University Hospital for comprehensive geriatric assessment were included in this cross-sectional study. Mean age of subjects were 72.30 ± 6.34 in osteoporosis group, 71.92 ± 6.90 in osteopenia and 71.86 ± 5.88 in control group (p: 0.260). Multivariate regression analysis revealed that hypertension (HT) (OR: 0.675, 95% CI: 0.534-0.854, p: 0.001), diabetes mellitus (DM) (OR: 1.669, 95% CI: 1.301-2.142, p: <0.001), age (OR: 1.025, 95% CI: 1.006-1.044, p: 0.009), male gender (OR: 0.451, 95% CI: 0.358-0.569, p<0.001), uric acid (OR: 0.893, 95% CI: 0.837-0.952, p: 0.001), hcy (OR: 1.042, 95% CI: 1.023-1.061, p<0.001), albumin (OR: 0.521, 95% CI: 0.376-0.724, p<0.001), GGT (OR: 1.010, 95% CI: 1.003-1.017, p: 0.003), creatinine (OR: 0.630, 95% CI: 0.459-0.864, p: 0.004) were independent variables predicting the occurrence of osteoporosis. This study shows there is an imbalance between natural antioxidative and oxidative markers in patients with osteoporosis. Higher serum uric acid and albumin levels are associated with a lower prevalence of osteoporosis whereas higher hcy and GGT levels are associated lower BMD and higher osteoporosis prevalence.


DNA-membrane complex restoration in Micrococcus radiodurans after X-irradiation: relation to repair, DNA synthesis and DNA degradation.
The DNA-membrane complex in Micrococcus radiodurans was shown to be essentially constituted of proteins, lipids and DNA. The complex was dissociated immediately after X-irradiation of cells and restored during post-incubation in complete medium. In X-irradiated protoplasts some DNA remained associated with the complex. Restoration of the complex during post-incubation was only seen in a medium favouring DNA polymerase and ligase activities. Under this condition no DNA synthesis occurred, suggesting that complex restoration may involve ligase activity. The complex restoration in the wild type and the X-ray sensitive mutant UV17 of M. radiodurans was strictly dependent on the X-ray dose. It was correlated with survival and DNA degradation but always preceded the onset of DNA synthesis after X-irradiation. At the same dose the complex restoration was about 2 fold lower in mutant than in wild type cells indicating that the restoration of the complex is related to repair capacity. The results are consistent with the idea that the complex protects X-irradiated DNA of M. radiodurans from further breakdown and, subsequently, permits DNA synthesis and repair to occur.


Renal replacement therapy in Kuwait.
The reported incidence of end-stage renal disease (ESRD) in Kuwait is 72 patients per million population per year. All modalities of dialysis therapy are available and are offered free of cost. There are 232 patients of whom 166 are on hemodialysis, five on hemofiltration, 45 on intermittent peritoneal dialysis and 16 on continuous ambulatory peritoneal dialysis. Chronic tubulo-interstitial disease resulting from atrophic pyelonephritis was the leading cause of ESRD in these patients. Nearly half of the patients on dialysis receive recombinant human erythropoietin. From 1979 until March 1990, 500 renal transplantations were performed in Kuwait of which 350 were performed using kidneys from live related donors, 100 from cadaveric donors, 50 from live unrelated, but emotionally related, donors. The limited pool of potential kidney donors continues to be a major problem. Our experience with imported cadaver kidneys showed that they were unsafe. Commercial kidney transplantation, in our experience, was associated with high morbidity and mortality rates. Despite the governmental laws, religious approval, and adequacy of transplantation facilities in Kuwait, the progress in the field of local organ procurement has remained very slow.


Pathogen Recognition-Driven Dendritic Cell-Specific Gene Silencing and Editing.
Dendritic cells (DCs) play an essential role in both the induction of the immune response and the maintenance of immune tolerance, with any malfunction of DCs potentially causing several diseases. While gene-based therapy for DC manipulation is a promising approach, it remains challenging due to the lack of efficient delivery systems for DC targeting. Herein, we describe a novel bacterial nanomedicine (BNM) system for pathogen recognition-mediated DCs-specific gene silencing and gene editing. BNMs contain components from bacterial outer membranes and achieve efficient DC targeting through the recognition of pathogen-associated molecular patterns by pattern recognition receptors on DCs. The targeting efficiency of BNMs is reduced in DCs lacking toll-like receptor 4, which is responsible for recognizing lipopolysaccharide, a major component of the bacterial outer membrane. As a proof-of-concept demonstration, we present gene-based therapy mediated by BNMs for enhancing antigen cross-presentation in DCs, which generates a remarkable antitumor effect.