Astaxanthin encapsulation in multilayer emulsions stabilized by complex coacervates of whey protein isolate and Persian gum and its use as a natural colorant in a model beverage.
Crustacean byproducts are valuable sources of astaxanthin. In this study, an astaxanthin-rich lipid phase was extracted from shrimp waste and encapsulated in multilayer emulsions. Stabilized by electrostatic complexes of whey protein isolate (WPI) and Persian gum (PG), the multilayer emulsions were created by different WPI:PG mixing ratios (1:2-1:4). The resultant emulsions were then exposed to lyophilization. The encapsulation efficiency of astaxanthin in lyophilized powders was 42.9-49.8 (g astaxanthin/100 g astaxanthin). The moisture content and water activity of the powders decreased significantly (p < 0.05), but their solubility and hygroscopicity increased significantly (p < 0.05) in response to an increase in the PG content of the mixture (or by reducing the WPI:PG ratio). Morphological characterizations revealed the formation of smaller and more uniform microcapsules when higher amounts of PG were used. Water dispersibility was higher than 94 (g powder/100 g powder). The results of an accelerated stability test showed an improvement in astaxanthin chemical stability in the multilayer emulsions, particularly when the WPI:PG ratio was 1:4. A model beverage consisting of water (89 g/100 g), sugar (10 g/100 g) and citric acid (1 g/100 g) was prepared and the potential application of astaxanthin microcapsules as a natural colorant was studied and compared with a synthetic colorant (E110) under the effect of light/darkness, temperature (4 and 25 °C) and time (0-60 d). The encapsulated lipid extract imparted a highly stable color to the product which was comparable to the effect of the synthetic colorant. However, the astaxanthin concentration was highly affected by time and partially affected by light and temperature.


Metabolic profiling in Caenorhabditis elegans provides an unbiased approach to investigations of dosage dependent lead toxicity.
The nematode, Caenorhabditis elegans (CE), serves as a model system in which to explore the impact of particularly low-levels of lead [250, 500, 1000 and 2000 parts per million (ppm) (1.4 × 10(-6) M to 1.1 × 10(-5) M/nematode)] on specific metabolic pathways and processes. Chromatographic profiles of redox active metabolites are captured through application of high performance liquid chromatography coupled to electrochemical detection (Coularray/HPLC). Principal Component Analysis (PCA: unbiased cluster analysis) and the application of a slicing program, located significant areas of difference occurring within the 2.8-4.58 min section of the chromatograms. It is within this region of the data profiles that known components of the purine pathway reside. Two analytes of unknown structure were detected at 3.5 and 4 min respectively. Alterations in levels of the purine, tryptophan and tyrosine pathway intermediates measured in response to differing concentrations of lead acetate indicate that the effect of lead on these pathways is not linear, yet the ratio of the pathway precursors, tryptophan and tyrosine remains relatively constant. The application of the above combined analytical approaches enhances the value of data generated. Exposure of CE to very low levels of lead produced significant alterations in profiles of electrochemically active compounds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-012-0438-0) contains supplementary material, which is available to authorized users.


Insomnia in patients with neurodegenerative conditions.
Comorbid insomnia and other sleep disturbances are common in patients with neurodegenerative disorders, such as Parkinson's or Alzheimer's disease. Insomnia in patients with neurological conditions may occur as a direct consequence of the disease itself or may be secondary to factors associated with the condition, such as pain, depression or the effects of medications. Disturbed sleep can have a significant impact on the patient's cognitive and physical function and may be associated with distress and depression. Insomnia also impacts patients' and caregivers' quality of life and is often cited as one of the primary reasons for patient institutionalization. Management of insomnia in patients with neurological disorders should be individualized to each patient's needs. The type of insomnia and any underlying causes of disturbed sleep must first be determined. Non-pharmacological interventions, such as behavioral modification, should be considered for all patients. Bright light therapy may be an effective treatment option for patients with disturbed sleep-wake patterns. Medications causing sleep problems should be withdrawn or doses and/or timing adjusted, whenever possible. Several pharmacological options are available to relieve the symptoms of insomnia as short-term treatment.


Theoretical and experimental indicators of falls during pregnancy as assessed by postural perturbations.
Throughout pregnancy, women experience physical, physiological, and hormonal alterations that are often accompanied by decreased postural control. According to one study, nearly 27% of pregnant women fell while pregnant. This study had two objectives: (1) to characterize the postural responses of pregnant fallers, nonfallers, and controls to surface perturbations, and (2) to develop a mathematical model to gain insights into the postural control strategies of each group. This retrospective analysis used experimental data obtained from 15 women with a fall history during pregnancy, 14 women without a fall history during pregnancy, and 40 nonpregnant controls. Small, medium, and large translational support surface perturbations in the anterior and posterior directions were performed during the pregnant participants' second and third trimesters. A two-segmented mathematical model of bipedal stance was developed and parameterized, and optimization tools were used to identify ankle and hip stiffness, viscosity, and the feedback time delay by searching for the best fits to experimental COP data. The peak differences between the center of pressure and center of gravity (COP-COG) values were significantly smaller for the pregnant fallers compared with the pregnant nonfallers and controls (p<0.01). Perturbation magnitude was a significant factor (p<0.01), but perturbation direction was not (p=0.24). Model fits were obtained with a mean goodness of fit value of R(2)=0.92. Theoretical results indicated that pregnant nonfallers had higher ankle stiffness compared with the pregnant fallers and the controls, which suggests that ankle stiffness itself may be the dominant reason for the different dynamic response characteristics (e.g., peak COP-COG) observed. We conclude that increasing ankle stiffness could be an important strategy to prevent falling by pregnant women.


Disordered intestinal function in glycogen storage disease.
The classical features of Type I glycogen storage disease (McKusick 23220) (GSD) are hepatomegaly, hypoglycaemia, and acidosis, enlargement of the kidneys and short stature. Glucose-6-phosphatase (EC 220.127.116.11) activity is defective not only in liver and kidney but also in small intestine (Field et al., 1965). In addition to the classical features, many patients suffer from episodes of diarrhoea (Fine et al., 1969). At the Hospital for Sick Children, Great Ormond Street, patients with the commoner forms of hepatic glycogen storage disease have episodes of diarrhoea or loose stools more commonly than was suspected. We have investigated small intestinal function in three patients with Type I GSD by both in vitro and in vivo techniques.


The development and characterization of in vivo-like three-dimensional models of bronchial epithelial cell lines.
In vitro models of differentiated respiratory epithelium that allow high-throughput screening are an important tool to explore new therapeutics for chronic respiratory diseases. In the present study, we developed in vivo-like three-dimensional (3-D) models of bronchial epithelial cell lines that are commonly used to study chronic lung disease (16HBE14o-, CFBE41o- and CFBE41o- 6.2 WT-CFTR). To this end, cells were cultured on porous microcarrier beads in the rotating wall vessel (RWV) bioreactor, an optimized suspension culture method that allows higher throughput experimentation than other physiologically relevant models. Cell differentiation was compared to conventional two-dimensional (2-D) monolayer cultures and to the current gold standard in the respiratory field, i.e. air-liquid interface (ALI) cultures. Cellular differentiation was assessed in the three model systems by evaluating the expression and localization of markers that reflect the formation of tight junctions (zonula occludens 1), cell polarity (intercellular adhesion molecule 1 at the apical side and collagen IV expression at the basal cell side), multicellular complexity (acetylated α-tubulin for ciliated cells, CC10 for club cells, keratin-5 for basal cells) and mucus production (MUC5AC) through immunostaining and confocal laser scanning microscopy. Results were validated using Western Blot analysis. We found that tight junctions were expressed in 2-D monolayers, ALI cultures and 3-D models for all three cell lines. All tested bronchial epithelial cell lines showed polarization in ALI and 3-D cultures, but not in 2-D monolayers. Mucus secreting goblet-like cells were present in ALI and 3-D cultures of CFBE41o- and CFBE41o- 6.2 WT-CFTR cells, but not in 16HBE14o- cells. For all cell lines, there were no ciliated cells, basal cells, or club cells found in any of the model systems. In conclusion, we developed RWV-derived 3-D models of commonly used bronchial epithelial cell lines and showed that these models are a valuable alternative to ALI cultures, as they recapitulate similar key aspects of the in vivo parental tissue.


Biomechanical properties of synthetic surgical meshes for pelvic prolapse repair.
Synthetic meshes are widely used for surgical repair of different kind of prolapses. In the light of the experience of abdominal wall repair, similar prostheses are currently used in the pelvic region, to restore physiological anatomy after organ prolapse into the vaginal wall, that represent a recurrent dysfunction. For this purpose, synthetic meshes are surgically positioned in contact with the anterior and/or posterior vaginal wall, to inferiorly support prolapsed organs. Nonetheless, while mesh implantation restores physiological anatomy, it is often associated with different complications in the vaginal region. These potentially dangerous effects induce the surgical community to reconsider the safety and efficacy of mesh transvaginal placement. For this purpose, the evaluation of state-of-the-art research may provide the basis for a comprehensive analysis of mesh compatibility and functionality. The aim of this work is to review synthetic surgical meshes for pelvic organs prolapse repair, taking into account the mechanics of mesh material and structure, and to relate them with pelvic and vaginal tissue biomechanics. Synthetic meshes are currently available in different chemical composition, fiber and textile conformations. Material and structural properties are key factors in determining mesh biochemical and mechanical compatibility in vivo. The most significant results on vaginal tissue and surgical meshes mechanical characterization are here reported and discussed. Moreover, computational models of the pelvic region, which could support the surgeon in the evaluation of mesh performances in physiological conditions, are recalled.


Phorbol ester enhances excitatory amino acid-induced dopamine release from mesencephalic cell cultures.
The hypothesis that protein kinase C activation can modulate excitatory amino acid-induced dopamine release was tested by investigating effects of phorbol esters, direct activators of protein kinase C, on dopamine release stimulated by N-methyl-D-aspartate (NMDA) and non-NMDA sub-types of excitatory amino acid agonists in fetal rat mesencephalic cell cultures. The phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (TPA), enhanced dopamine release evoked by NMDA, kainate, quisqualate and by K+ depolarization. Release in the presence of NMDA and TPA was completely abolished by the NMDA antagonist, MK-801. TPA enhancement of NMDA-stimulated dopamine release was likely due to protein kinase C activation by the phorbol ester since (1) the NMDA response was enhanced by nanomolar concentrations of TPA, (2) two phorbol esters capable of activating protein kinase C enhanced the NMDA response while an inactive phorbol ester did not, (3) staurosporine, a potent protein kinase C inhibitor, blocked TPA enhancement of the NMDA response. TPA enhancement of NMDA-stimulated dopamine release was not blocked by H8, an inhibitor with high affinity for cyclic nucleotide dependent kinases, while forskolin, a direct activator of adenylate cyclase, had no effect on NMDA-stimulated release, indicating a lack of involvement of cAMP-dependent kinase in the TPA effect. TPA enhanced NMDA-stimulated release both in the presence and absence of Mg2+, indicating that TPA enhancement was not due to reversal of a Mg2+ blockade of the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)


Personality assessments and outcomes in medical education and the practice of medicine: AMEE Guide No. 79.
In a paradigm of physician performance we propose that both "cognitive" and "noncognitive" components contribute to the performance of physicians-in-training and in-practice. Our review of the relevant literature indicates that personality, as an important factor of the "noncognitive" component, plays a significant role in academic and professional performances. We describe findings on 14 selected personality instruments in predicting academic and professional performances. We question the contention that personality can be validly and reliably assessed from admission interviews, letters of recommendation, essays, and personal statements. Based on conceptual relevance and currently available empirical evidence, we propose that personality attributes such as conscientiousness and empathy should be considered among the measures of choice for the assessment of pertinent aspects of personality in academic and professional performance. Further exploration is needed to search for additional personality attributes pertinent to medical education and patient care. Implications for career counseling, assessments of professional development and medical education outcomes, and potential use as supplementary information for admission decisions are discussed.


Critical behavior of thermal relaxation near a breakdown point.
At a composition far above the percolation threshold, the resistance of a composite sample increases with time due to Joule heating as a constant current of a sufficiently large value is passed through the sample. If the current is less than a certain breakdown current (I(b)) the resistance eventually reaches a steady value with a characteristic relaxation time tau(h). The latter diverges with current I as tau(h) approximately (1-I(2)/I(2)(b))(-z). The value of the exponent z displays large fluctuations leading to unusual scaling of the relaxation time. It is shown that the results lead to important conclusions about the nature of breakdown phenomena.


The dynamics of mast cell secretion studied by vital berberine staining.
The fluorescent cationic dye berberine in combination with histamine release studies have been used to explore the different steps of the mast cell secretory process. We have previously shown that quantitation of heparin release by the binding of berberine to fixed mast cells can be used as a direct measure of release of granules. This report summarizes recent work using berberine as a vital stain demonstrating the secretory activity of mast cells. After membrane stabilization with polyethylene glycol (PEG) normal mast cells exclude the dye while mast cells stimulated to secretion with polymyxin B show a strongly fluorescent dye binding to individual cytoplasmic granules. The mean fluorescence intensity of the cell populations after vital berberine staining was compared both to heparin and histamine release. The results strongly suggest that berberine, under the vital staining conditions used, is a marker of intracellular granules that have released histamine. The vital staining method was also used to study membrane events following a polymyxin B-induced secretion. The mean fluorescence intensity decreased by 75% during the first hour after the termination of a polymyxin B stimulation while the mast cell content of histamine and heparin remained constant. The findings support the idea that the membranes are rapidly restored after mast cell secretion, permitting a selective amine release without accompanying release of heparin or other matrix components of the granules.


Bacteriophage P22 Mnt repressor. DNA binding and effects on transcription in vitro.
We have examined the binding of Mnt repressor to operator DNA in vitro and have determined how this binding affects the level of transcription from two nearby promoters, Pant and Pmnt. Mnt binds to a region of DNA that overlaps the startpoint of transcription of Pant and the -35 region of Pmnt. Mnt represses transcription in vitro from Pant and enhances transcription from Pmnt. Protection and interference experiments show that Mnt binds to a single, 17 base-pair operator site. The operator sequence and the protein-DNA contacts are symmetric. Mnt makes major groove contacts on both faces of the operator DNA. At pH 7.5, 200 mM-KCl, 22 degrees C, the Mnt tetramer binds operator with high affinity (Kd = 2.2 X 10(-11M) and the protein-DNA complex is quite stable (t1/2 = 48 min). Operator binding shows large dependencies on pH, salt concentration, and temperature.


80% of muscarinic receptors expressed by the NB-OK 1 human neuroblastoma cell line show high affinity for pirenzepine and are comparable to rat hippocampus M1 receptors.
The NB-OK 1 human neuroblastoma cell line expressed muscarinic cholinergic receptors that could be labeled with N-[3H]methylscopolamine (a nonselective antagonist). 80% of these receptors showed high affinity for pirenzepine, i.e. belonged to the M 1 subtype found in neuronal tissues. Their binding properties were identical to those of rat hippocampus M 1 receptors, and differed from those of rat pancreas and heart muscarinic receptors. The remaining (20%) muscarinic receptors showed low affinity for pirenzepine and AF-DX 116, being therefore of an M2 beta (or B) subtype, and were similar to rat pancreatic receptors.


Clinical and Research Criteria for Developmental Coordination Disorder-Should They Be One and the Same?
The aim of this paper is to discuss if criteria used for diagnosing children for clinical purposes should be the same as for the selection of children with Developmental Coordination Disorder for research. Next, we give an overview of the criteria mentioned in the development of the European guideline for diagnosing Developmental Coordination Disorder and the implementation of this guideline in different countries. To gain insight into current clinical practice, we also reviewed the medical files of children attending rehabilitation centers for the criteria used to diagnose Developmental Coordination Disorder in the Netherlands. To conclude, we state our expert opinion on why and when research and clinical criteria for Developmental Coordination Disorder should or should not be the same.


Ornithine aminotransferase deficiency: diagnostic difficulties in neonatal presentation.
We describe two unrelated cases of ornithine aminotransferase (OAT) deficiency with rare neonatal presentation of hyperammonaemia. The diagnosis in the neonatal presentation of OAT deficiency is hampered as hyperornithinaemia is absent. Enzyme and mutation studies confirmed the diagnosis. OAT deficiency should be included in differential diagnosis of neonatal hyperammonaemia.


The role of counseling in infertility.
Sixty-two couples with infertility received infertility counseling along with the infertility investigation and treatment. At the end of the study a questionnaire was sent to all patients in order to evaluate the incidence of psychologic symptoms associated with their infertility and their response to counseling. The study confirmed the presence of a high incidence of emotional symptomatology in the self-selected patients. It showed that male partners are also affected, but less so. Finally, it has demonstrated that infertility counseling serves to enhance the quality of life in many patients who have become the victims of their "infertility crises."


Enterococcus gallinarum endocarditis in a diabetic patient.
Recent studies pointed out the increasing rate of infective endocarditis (IE) in diabetic patients. As diabetes mellitus (DM) prevalence is expected to increase in the coming years, infective endocarditis could be more frequently reported in these patients. We here describe a rare case of Enterococcus gallinarum endocarditis developing on normal native heart valve in an elderly diabetic woman. Therapeutic options were restricted due to resistance factors of the microorganism, limited guidance in the medical literature, and the patient's history and underlying condition. Despite these challenges, adequate antibiotic therapy led to the patient's recovery.


Motif detection in quantum noise-limited electron micrographs by cross-correlation.
The use of cross-correlation to detect randomly positioned low-dose realizations of a motif in an image field is quantitatively evaluated. For both the bright- and dark-field cases, we derive theoretical expressions for the minimum dose allowing detection in terms of motif size, resolution, and contrast. Model computations on simulated low-dose images of a spherical virus particle give results that agree with our theoretical formulas and demonstrate the feasibility of this approach.


Stability of solvent/detergent-treated plasma and single-donor fresh-frozen plasma during 48 h after thawing.
The aim of this study was to compare the quality of solvent/detergent (SD) treated plasma, Octaplas, and single-donor fresh-frozen plasma (FFP) units during 48-h storage after thawing. Octaplas bags of different blood groups and individual FFP units were thawed and stored at either +4 degrees C or at room temperature (RT) for 48 h. Samples drawn during the observation period were investigated on various coagulation factor and protease inhibitor activities using standard coagulation and chromogenic assays. The generation of FVIIa was followed as a marker of coagulation factor activation. All investigated coagulation factors and protease inhibitors were stable for at least 8h during storage of Octaplas at +4 degrees C. FVIII levels started to decline earlier in FFP than in Octaplas at both storage temperatures. Stored Octaplas OD660 values were more stable during the storage period than FFP OD660 values, whereas VWF multimeric patterns were comparably stable in both types of plasma. In conclusion, this stability study has demonstrated that thawed Octaplas maintains its high quality, even with a time safety margin, for 8 h at +4 degrees C and for 6 h at RT. In general, there was more variability in coagulation factor levels among different FFP units compared with different Octaplas batches.


Maternal particulate matter exposure and gestational diabetes mellitus: a population-based cohort study.
Gestational diabetes mellitus prevalence is steadily increasing worldwide, posing a significant threat to the short-term and long-term health of both mother and offspring. Because particulate matter air pollution has been reported to affect glucose metabolism, it was suggested that maternal particulate matter exposure may be associated with the development of gestational diabetes mellitus; however, the evidence is limited and inconsistent. This study aimed to determine the association between maternal exposure to particulate matter of diameter ≤2.5 µm and of diameter of ≤10 µm and the risk of gestational diabetes mellitus, to identify critical windows of susceptibility and to evaluate effect modification by ethnicity. A retrospective cohort study was conducted including pregnancies of women who delivered at a large tertiary medical center in Israel between 2003 and 2015. Residential particulate matter levels were estimated by a hybrid spatiotemporally resolved satellite-based model at 1 km spatial resolution. Multivariable logistic analyses were applied to study the association between maternal particulate matter exposure in different pregnancy periods and gestational diabetes mellitus risk, while adjusting for background, obstetrical, and pregnancy characteristics. Analyses were also stratified by ethnicity (Jewish and Bedouin). The study included 89,150 pregnancies, of which 3245 (3.6%) were diagnosed with gestational diabetes mellitus. First trimester exposure to both particulate matter of diameter ≤2.5 µm (adjusted odds ratio per 5 μg/m3, 1.09; 95% confidence interval, 1.02-1.17) and particulate matter of diameter of ≤10 µm (adjusted odds ratio per 10 μg/m3, 1.11; 95% confidence interval, 1.06-1.17) was significantly associated with increased risk for gestational diabetes mellitus. In the stratified analyses, the association with first trimester particulate matter of diameter of ≤10 µm exposure was consistent among pregnancies of both Jewish and Bedouin women, whereas the association with first trimester particulate matter of diameter ≤2.5 µm exposure was significant among pregnancies of Jewish women only (adjusted odds ratio per 5 μg/m3, 1.09; 95% confidence interval, 1.00-1.19), as well as association with preconception particulate matter of diameter of ≤10 µm exposure (adjusted odds ratio per 10 μg/m3, 1.07; 95% confidence interval, 1.01-1.14). No association was found between second trimester particulate matter exposure and gestational diabetes mellitus risk. Maternal exposure to both particulate matter of diameter ≤2.5 µm and diameter of 10 µm or less during the first trimester of pregnancy is associated with gestational diabetes mellitus, suggesting that the first trimester is a particular window of susceptibility to the effect of particulate matter exposure on gestational diabetes mellitus risk. The effects found in this study differed by ethnic group, emphasizing the importance of addressing ethnic disparities when assessing environmental impacts on health.


Intravitreous granulation tissue and retinal detachment following pars plana injection for cytomegalovirus retinopathy.
Recently, the pars plana route of injection has been used to administer drugs for the treatment of severe intraocular infections. We observed a complication of this method in a patient with AIDS and cytomegalovirus (CMV) retinopathy.


Separation and preconcentration of arsenite and other heavy metal ions using graphene oxide laminated with protein molecules.
The graphene oxide surface was laminated with bovine serum albumin (BSA) followed by the directional flow through a membrane to prepare a free-standing PLGO (protein laminated GO) composite. BSA immobilization increased the interlayer spacing of GO and led to the formation of capillaries. The column packed with PLGO adsorbent permeated water faster as much as ca. 5 fold as compared to only GO packed column. The PLGO composite was used to develop a solid phase extraction method for the selective preconcentration of As(III) in the presence of As(V), prior to their determination. As(III) binding to sulfhydryl groups of BSA in PLGO plays a key role in the speciation. The coexisting heavy metal ions did not hinder the recovery of trace As(III). The method was advantageously employed for the preconcentration of As(III), Pb(II), Cd(II), Zn(II), Cu(II) and Ni(II) from water and food samples. A 3 mL of 1 M hydrochloric acid would be adequate for the complete desorption (recovery > 99%) of the adsorbed metal ions. The preconcentration limit achieved for As(III), Pb(II), Cd(II), Zn(II), Cu(II) and Ni(II) were 1.7, 2.0, 2.0, 2.0, 1.8 and 2.0 μg L-1 respectively, with an optimized sample flow rate of 10 mL min-1.


A polymerase chain reaction-based approach to cloning sigma factors from eubacteria and its application to the isolation of a sigma-70 homolog from Chlamydia trachomatis.
Taking advantage of the known sequence conservation of portions of bacterial sigma factor proteins, we have designed degenerate oligonucleotides corresponding to these domains and used these synthetic DNA sequences as primers in a polymerase chain reaction (PCR) to amplify DNA sequences from the chlamydial genome. The PCR products were used as a probe to recover the genomic fragments from a library of cloned murine Chlamydia trachomatis DNA. Sequence analysis of one of these clones revealed striking homology to the sigma-70 protein of Escherichia coli and the sigma-43 protein of Bacillus subtilis, strongly implying that this locus (sigA) encodes the major vegetative sigma factor of murine C. trachomatis. This PCR-based approach will be broadly applicable to the cloning of major sigma factors from other eubacteria.


Angiotensin-converting enzyme inhibitor (ACE-I)- and angiotensin receptor blocker (ARB)-related angioedema: a neglected issue in daily practice in Greece.
Several reports on angioedema (AE) related to the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have been published recently. This study reports on the experience gained at the Ear, Nose, and Throat (ENT) Clinic of the University Hospital of Heraklion, Crete. A retrospective chart review of the patients admitted to this clinic, in a 42-month period (1999-2003), and discharged with a diagnosis ENT code for AE was performed (14 eligible patients). A complementary telephone survey was conducted during January 2005. Ten patients responded to our invitation. Of those patients, five were under ACE-I and one was under ARB treatment during the AE episode. The mean length of time between the onset of symptoms and presentation to the hospital was 4.5 hours (range 0.5-12 hours). The mean duration between the initiation of antihypertensive treatment and AE episode was 26.2 months (range 1-60 months). Patients reported that no information was provided about the possible adverse effects of these drugs. Although AE introduced by ACE-I and ARBs is an uncommon side effect, this case series conveys a key message to primary care physicians.


Fabrication, structural characterization and functional attributes of polysaccharide-surfactant-protein ternary complexes for delivery of curcumin.
In this study, the nanocomplexes as a novel delivery system for curcumin, were successfully fabricated using high methoxyl pectin (HMP), individual surfactants (rhamnolipid (Rha), tea saponin (TS) and ethyl lauroyl arginate hydrochloride (ELA)) and pea protein isolate (PPI). The optimum mass ratio between PPI and curcumin was 40:1. The HMP-Rha-PPI-Cur, HMP-TS-PPI-Cur and HMP-ELA-PPI-Cur complexes which had particle sizes of 453, 422 and 587 nm, exhibited encapsulation efficiencies of curcumin with 93.46, 92.05 and 86.73%, respectively. The analysis of FTIR revealed that HMP-surfactant-PPI-Cur complexes were formed mainly by hydrogen bonding and electrostatic attraction. XRD result showed that curcumin exhibited a non-crystallized state in the ternary complexes. Moreover, the curcumin within the HMP-Rha-PPI ternary complexes showed better stability under UV-light, thermal and simulated gastrointestinal conditions.


Simple and rapid HPLC method for simultaneous determination of atenolol and chlorthalidone in spiked human plasma.
A simple, sensitive and rapid chromatographic method was developed and validated for the simultaneous quantification of atenolol and chlorthalidone in human plasma using hydrochlorothiazide as internal standard (IS). The method utilized proteins precipitation with acetonitril as the only sample preparation involved prior to reverse phase-HPLC. The analytes were chromatographed on Shim-pack cyanopropyl column with isocratic elution with 10 mM KH2PO4 (pH 6.0) - methanol (70:30, v/v) at ambient temperature with flow rate of 1 mL min(-1) and UV detection at 225 nm. The chromatographic run time was less than 10 min for the mixture. The calibration curves were linear over the range of 0.1-10 μg mL(-1). The method was validated in terms of accuracy, precision, absolute recovery, freeze-thaw stability, bench-top stability and re-injection reproducibility. The within- and between-day accuracy and precision were found to be within acceptable limits <15%. The analytes were stable after three freeze-thaw cycles (deviation <15%). The proposed method was specific for the simultaneous determination of atenolol and chlorthalidone in human plasma where there was no interference from endogenous biological substances.


[Comparative evaulation of different methods of draining the mediastinum in treating posterior suppurative mediastinitis].
A comparative study of the effectiveness of various methods of the drainage of the mediastinum was carried out on the grounds of the analysis of the clinical course and lethality in two groups of patients. The drainage of the mediastinum by means of two double-gap silicon tubes, followed by flowing-fractional washing and aspiration from the purulent cavity, applied in 40 patients, proved to be the most effective.


Neutrophil Interaction with Emerging Oral Pathogens: A Novel View of the Disease Paradigm.
Periodontitis is a multifactorial chronic inflammatory infectious disease that compromises the integrity of tooth-supporting tissues. The disease progression depends on the disruption of host-microbe homeostasis in the periodontal tissue. This disruption is marked by a shift in the composition of the polymicrobial oral community from a symbiotic to a dysbiotic, more complex community that is capable of evading killing while promoting inflammation. Neutrophils are the main phagocytic cell in the periodontal pocket, and the outcome of the interaction with the oral microbiota is an important determinant of oral health. Novel culture-independent techniques have facilitated the identification of new bacterial species at periodontal lesions and induced a reappraisal of the microbial etiology of periodontitis. In this chapter, we discuss how neutrophils interact with two emerging oral pathogens, Filifactor alocis and Peptoanaerobacter stomatis, and the different strategies deploy by these organisms to modulate neutrophil effector functions, with the goal to outline a new paradigm in our knowledge about neutrophil responses to putative periodontal pathogens and their contribution to disease progression.


The 2 A resolution structure of the sulfate-binding protein involved in active transport in Salmonella typhimurium.
The crystal structure of the liganded form of the sulfate-binding protein, an initial receptor for active transport of sulfate in Salmonella typhimurium, has been solved and refined at 2.0 A resolution (1 A = 0.1 nm). The final model, which consists of 2422 non-hydrogen atoms, one sulfate substrate and 143 water molecules, yields a crystallographic R-factor of 14.0% for 16,959 reflections between 8 and 2 A. The structure deviates from ideal bond lengths and angle distances by 0.015 A and 0.037 A, respectively. The protein is ellipsoid with overall dimensions of 35 A x 35 A x 65 A and consists of two similar globular domains. The two domains are linked by three distinct peptide segments, which though widely separated in the amino acid sequence, are in close proximity in the tertiary structure. As these connecting segments are located near the periphery of the molecule, they further serve as the base or a "boundary" of the deep cleft formed between the two domains. Despite the unusual interdomain connectivity, both domains have similar supersecondary structure consisting of a central five-stranded beta-pleated sheet sandwiched by alpha-helices on either side. The arrangement of the two domains gives rise to the ellipsoidal shape and to the cleft between the two domains wherein the sulfate substrate is found and completely engulfed. A discovery of considerable importance is that the sulfate substrate is tightly held in place primarily by seven hydrogen bonds, five of which are donated by main-chain peptide NH groups, another by a serine hydroxyl and the last by the indole NH moiety of a tryptophan side-chain; there are no positively charged residues, nor cations, nor water molecules within van der Waals' distance to the sulfate dianion. All the main-chain peptide units associated with the sulfate are in turn linked (via the peptide CO group) to arrays of hydrogen bonds. Three of these arrays are composed of alternating peptide units and hydrogen bonds within the solvent-exposed part of three alpha-helices and two are linked to a histidine and an arginine residue. The sulfate-binding protein bears strong similarity to the structures of four other periplasmic binding proteins solved in our laboratory which are specific for L-arabinose, D-galactose/D-glucose, leucine/isoleucine/valine and leucine. The similarity includes the ellipsoidal shape and the two globular domain structures, each domain consisting of a central beta-pleated sheet flanked by alpha-helices.(ABSTRACT TRUNCATED AT 400 WORDS)


Enumeration and identification of Aspergillus group and Penicillium species in poultry feeds from Argentina.
A total of 180 samples of poultry feeds were collected during 1996 and 1997 from different factories in the south of the province of Córdoba-Argentina. They were examined for the occurrence of Penicillium spp. and Aspergillus group species. Likewise, the capacity to produce aflatoxins by the Aspergillus section flavi group was determined. The predominant species of Aspergillus were A. flavus and A. parasiticus. For Penicillium spp., P. brevicompactum, P. purpurogenum and P. oxalicum were identified. Less frequently isolated were A. candidus, A. fumigatus, A. niger, A. orizae, A. parvulus, A. tamarii, A. terreus, and P. expansum, P. funiculosum, P. minioluteum, P. pinophylum, P. restrictum, P. variable and others. The mean value counts ranged from 1 x 10(3) to 9.5 x 10(4) CFU/g for the Aspergillus spp. and from 1.2 x 10(3) to 2.5 x 10(5) CFU/g for the Penicillium spp. When cultured on autoclaved rice kernels for 1 week in the dark at 25 degrees C, mycotoxin production by strains of A. flavus was as follows: 21 of the 45 assayed strains (47%) produced aflatoxins. From them, 24% of the isolates produced AFB1 and AFB2 with levels from 181 to 14545 and 6 to 3640 micrograms/kg respectively. Only 10 strains produced AFB1 with levels from 10 to 920 micrograms/kg. Fifty percent of the A. parasiticus strain was toxicogenic; six aflatoxicogenic profiles were identified. Only 10% of the strains produced all of the aflatoxins. These results showed that a potential exists for the production of mycotoxins by the Aspergillus section flavi and the Penicillium spp. They also suggested an association of mycotoxicosis with poultry feeds in Argentina.


Axillary dissection can be avoided in the majority of clinically node-negative patients undergoing breast-conserving therapy.
The extent to which ACOSOG Z0011 findings are applicable to patients undergoing breast-conserving therapy (BCT) is uncertain. We prospectively assessed how often axillary dissection (ALND) was avoided in an unselected, consecutive patient cohort meeting Z0011 eligibility criteria and whether subgroups requiring ALND could be identified preoperatively. Patients with cT1,2cN0 breast cancer undergoing BCT were managed without ALND for metastases in <3 sentinel nodes (SNs) and no gross extracapsular extension (ECE). Patients with and without indications for ALND were compared using Fisher's exact and Wilcoxon rank sum tests. From August 2010 to November 2012, 2,157 invasive cancer patients had BCT. A total of 380 had histologic nodal metastasis; 93 did not meet Z0011 criteria. Of 287 with ≥1 H&E-positive SN (209 macrometastases), 242 (84 %) had indications for SN only. ALND was indicated in 45 for ≥3 positive SNs (n = 29) or ECE (n = 16). The median number of SNs removed in the SN group was 3 versus 5 in the ALND group (p < 0.0001). Age, hormone receptor and HER2 status, and grade did not differ between groups; tumors were larger in the ALND group (p < 0.0001). Of ALND patients, 72 % had additional positive nodes (median = 1; range 1-19). No axillary recurrences have occurred (median follow-up, 13 months). ALND was avoided in 84 % of a consecutive series of patients having BCT, suggesting that most patients meeting ACOSOG Z0011 eligibility have a low axillary tumor burden. Age, ER, and HER2 status were not predictive of ALND, and the criteria used for ALND (≥3 SNs, ECE) reliably identified patients at high risk for residual axillary disease.


Te(II)/Te(IV) Mediated C-N Bond Formation on 2,5-Diphenyltellurophene and a Reassignment of the Product from the Reaction of PhI(OAc)2 with 2 TMS-OTf.
We report a novel C-H to C-N bond metathesis at the 3-position of 1,2-diphenyltellurophene via oxidation of the Te(II) center to Te(IV) using the I(III) oxidant [PhI(4-DMAP)2](2+). Spontaneous reduction of a transient Te(IV) coordination compound to Te(II) generates an electrophilic equivalent of 4-DMAP that substitutes at a C-H bond at the 3-position of the tellurophene. Theoretical and synthetic reaction pathway studies confirm that a Te(IV) coordination complex with 4-DMAP is an intermediate. In the course of these pathway studies, it was also found that the identity of the I(III) oxidant generated from PhI(OAc)2 and 2 TMS-OTf is PhI(OAc)(OTf) and not PhI(OTf)2, as had been previously thought.


Potential biomarkers for distinguishing primary from acquired premature ejaculation: A diffusion tensor imaging based network study.
Premature ejaculation (PE) is classified as primary and acquired and may be facilitated by different pathophysiology. Brain plays an important role in PE, however, differences in the central neuropathological mechanisms among subtypes of PE are unknown. We acquired diffusion tensor imaging (DTI) data from 44 healthy controls (HC) and 47 PE patients (24 primary PE and 23 acquired PE). Then, the whole-brain white matter (WM) structural networks were constructed and between-group differences of nodal segregative parameters were identified by the method of graph theoretical analysis. Moreover, receiver operating characteristic (ROC) curves were performed to determine the suitability of the altered parameters as potential neuroimaging biomarkers for distinguishing primary PE from acquired PE. PE patients showed significantly increased clustering coefficient C(i) in the left inferior frontal gyrus (triangular part) (IFGtriang.L) and increased local efficiency E loc (i) in the left precental gyrus (PreCG.L) and IFGtriang.L when compared with HC. Compared to HC, primary PE patients had increased C(i) and E loc (i) in IFGtriang.L and the left amygdala (AMYG.L) while acquired PE patients had increased C(i) and E loc (i) in IFGtriang.L, and decreased C(i) and E loc (i) in AMYG.L. Compared to acquired PE, primary PE patients had increased C(i) and E loc (i) in AMYG.L. Moreover, ROC analysis revealed that PreCG.L, IFGtriang.L and AMYG.L might be helpful for distinguishing different subtypes of PE from HC (PE from HC: sensitivity, 61.70-78.72%; specificity, 56.82-77.27%; primary PE from HC: sensitivity, 66.67-87.50%; specificity, 52.27-77.27%; acquired PE from HC: sensitivity, 34.78-86.96%; specificity, 54.55-100%) while AMYG.L might be helpful for distinguishing primary PE from acquired PE (sensitivity, 83.33-91.70%; specificity, 69.57-73.90%). These findings improved our understanding of the pathophysiological processes that occurred in patients with ejaculatory dysfunction and suggested that the abnormal segregation of left amygdala might serve as a useful marker to help clinicians distinguish patients with primary PE from those with acquired PE.


Disease course in mdx:utrophin+/- mice: comparison of three mouse models of Duchenne muscular dystrophy.
The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin(-/-) (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin(+/-) mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin(+/-) mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin(+/-), and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin(+/-) mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin(+/-) mice compared to mdx mice at 12 months. Mdx:utrophin(+/-) mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin(+/-) muscle compared to mdx at most ages examined. Generally, mdx:utrophin(+/-) mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin(+/-) mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus.


Lectin binding sites in normal and phenobarbitale/halothane treated rat liver. A histochemical study.
The content of carbohydrate residues of both normal and phenobarbitale-halothane-hypoxia exposed rat liver has been examined by means of lectin histochemistry. Eight biotinylated lectins specific to galactose, N-acetyl-galactosamine, N-acetyl-glucosamine, fucose and mannose were applied to paraffin sections of rat liver at light microscopic level. The most distinct binding was observed at the structures of the "perisinusoidal functional unit": Kupffer cells are bound by S-WGA, SBA and PNA. Bile canaliculi display binding sites for RCA I and WGA. Cytoplasm of hepatocytes appears lectin-negative, except for PSA. The enhanced reaction of S-WGA, PNA and SBA after the preincubation of the sections with neuraminidase indicates the occurrence of sialic acid in Kupffer cells. The phenobarbitale-halothane-hypoxia exposed rat liver shows centrolobular degeneration of hepatocytes with a diminished amount of hepatocyte and Kupffer cells as well. The lectin binding pattern of sinusoidal walls, membranes of hepatocytes and bile canaliculi remains the same compared to that of normal rat liver. This finding suggests that at least the carbohydrate content of membranes in the liver resists severe destruction under phenobarbitale-halothane-hypoxia. It is assumed that there exists a connection between intact carbohydrate residues and the regeneration of liver parenchyma.


Exterior air quality monitoring for the Eurasia Tunnel in Istanbul, Turkey.
Traffic is a major concern for the city of Istanbul due to the rapid increase in population and car ownership. Eurasia Tunnel, which has a capacity around 100,000 light vehicles/day, is the fourth highway link between Asia and Europe, established to relieve the existing pressure on the transport system. As an important alternative to other Bosphorus Strait crossings, the tunnel offers directly reduced traffic durations in the city especially during rush hours and indirectly provides reduced fuel consumption, thereby less harmful gas emissions into the atmosphere. The main objective of this study is to evaluate the air quality effects of the Eurasia Tunnel on the city of Istanbul through investigating the air quality 1 year before and 2 years after operation, and comparing the hourly and daily pollutant levels with tunnel traffic. Monitoring data were examined to detect the relationships between selected pollutant concentrations, to evaluate meteorology effects on the pollutants and to identify air quality impact of the Eurasia Tunnel. Analyses revealed that air pollutants concentrations do not increase with increase in tunnel traffic. Moreover, since the tunnel entered operation, average hourly CO, PM10 and PM2.5 concentrations at monitoring stations located close to the stacks have decreased 16-30%, 44-46% and 12-24%, respectively. Average NO2 concentrations increased about 9-24%, but these concentrations still remain below the 1-hour standard. All in all, Eurasia Tunnel has no significant effect on the Istanbul's air quality.


Artificial Shape Perception Retina Network Based on Tunable Memristive Neurons.
Retina shows an extremely high signal processing efficiency because of its specific signal processing strategy which called computing in sensor. In retina, photoreceptor cells encode light signals into spikes and ganglion cells finish the shape perception process. In order to realize the neuromorphic vision sensor, the one-transistor-one-memristor (1T1M) structure which formed by one memristor and one MOSFET in serial is used to construct photoreceptor cell and ganglion cell. The voltage changes between two terminals of memristor and MOSFET can mimic the changes of membrane potential caused by spikes and illumination respectively. In this paper, the tunable memristive neurons with 1T1M structures are built. According to the concept of receptive field of ganglion cells (GCs) in the retina, the artificial shape perception retina network is constructed with these memristive neurons. The final results show that the artificial retina can extract shape information from the image and transfer it into spike frequency realizing the function of computing in sensor.


Thrombus Burden and Outcomes in Patients With COVID-19 Presenting With STEMI Across the Pandemic.
It has been previously reported during the first COVID-19 outbreak that patients presenting with ST-segment elevation myocardial infarction (STEMI) and concurrent COVID-19 infection have increased thrombus burden and poorer outcomes. To date, there have been no reports comparing the outcomes of COVID-19-positive STEMI patients across all waves of the pandemic. This study compared the baseline demographic, procedural, and angiographic characteristics alongside the clinical outcomes of patients presenting with STEMI and concurrent COVID-19 infection across the COVID-19 pandemic in the United Kingdom. This was a single-center, observational study of 1,269 consecutive patients admitted with confirmed STEMI treated with percutaneous coronary intervention (between January 3, 2020 and October 3, 2022). COVID-19-positive patients were split into 3 groups based upon the time course of the pandemic, and a comparison was made between waves. A total of 154 COVID-19-positive patients with STEMI were included in the present analysis and were compared with 1,115 COVID-19-negative patients. Early during the pandemic (wave 1), STEMI patients presenting with concurrent COVID-19 infection had high rates of cardiac arrest, evidence of increased thrombus burden, bigger infarcts, and worse outcomes. However, by wave 3, no differences existed in outcomes between COVID-19-positive and -negative patients, with significant differences compared with earlier COVID-19-positive patients. Poor outcomes later in the study period were predominantly in unvaccinated individuals. Significant changes have occurred in the clinical characteristics, angiographic features, and outcomes of STEMI patients with COVID-19 infection treated by primary percutaneous coronary intervention during the course of the pandemic. Importantly, outcomes of recent waves and in vaccinated individuals are no different to a non-COVID-19 population.


Changes in circulatory white blood cells of mice and rats due to acute trichothecene intoxication.
In mice, administration of pure T-2 toxin caused a rapid decrease of lymphocyte counts, which was linear with respect to dose, whereas granulocyte counts showed a delayed decrease. The blood cell counts of both cell types attained normal values after 4-7 days. Similar results were obtained for crude A-, B- and macrocyclic type trichothecene. Intoxication of rats with T-2 toxin or crude A-type trichothecene caused changes in white blood cells, which differed quantitatively from those in the mouse: lymphocyte counts decreased less and a rapid transient increase of granulocytes was more obvious. Results of this study show that lymphocyte and granulocyte blood cell counts of small rodents respond sensitively to acute intoxication with various trichothecenes.


Cerebral blood flow in schizophrenia: A systematic review and meta-analysis of MRI-based studies.
Schizophrenia-spectrum disorders (SSD) represent one of the leading causes of disability worldwide and are usually underpinned by neurodevelopmental brain abnormalities observed on a structural and functional level. Nuclear medicine imaging studies of cerebral blood flow (CBF) have already provided insights into the pathophysiology of these disorders. Recent developments in non-invasive MRI techniques such as arterial spin labeling (ASL) have allowed broader examination of CBF across SSD prompting us to conduct an updated literature review of MRI-based perfusion studies. In addition, we conducted a focused meta-analysis of whole brain studies to provide a complete picture of the literature on the topic. A systematic OVID search was performed in Embase, MEDLINEOvid, and PsycINFO. Studies eligible for inclusion in the review involved: 1) individuals with SSD, first-episode psychosis or clinical-high risk for psychosis, or; 2) had healthy controls for comparison; 3) involved MRI-based perfusion imaging methods; and 4) reported CBF findings. No time span was specified for the database queries (last search: 08/2022). Information related to participants, MRI techniques, CBF analyses, and results were systematically extracted. Whole-brain studies were then selected for the meta-analysis procedure. The methodological quality of each included studies was assessed. For the systematic review, the initial Ovid search yielded 648 publications of which 42 articles were included, representing 3480 SSD patients and controls. The most consistent finding was that negative symptoms were linked to cortical fronto-limbic hypoperfusion while positive symptoms seemed to be associated with hyperperfusion, notably in subcortical structures. The meta-analysis integrated results from 13 whole-brain studies, across 426 patients and 401 controls, and confirmed the robustness of the hypoperfusion in the left superior and middle frontal gyri and right middle occipital gyrus while hyperperfusion was found in the left putamen. This updated review of the literature supports the implication of hemodynamic correlates in the pathophysiology of psychosis symptoms and disorders. A more systematic exploration of brain perfusion could complete the search of a multimodal biomarker of SSD.


Hh-induced Smoothened conformational switch is mediated by differential phosphorylation at its C-terminal tail in a dose- and position-dependent manner.
The activation of Smoothened (Smo) requires phosphorylation at three clusters of Serine residues in Drosophila Hedgehog (Hh) signaling. However, the mechanism by which phosphorylation promotes Smo conformational change and subsequently activates Smo in response to Hh gradient remains unclear. Here, we show that the conformational states of Smo are determined by not only the amount but also the position of the negative charges provided by phosphorylation. By using a Smo phospho-specific antibody, we demonstrate that Smo is differentially phosphorylated at three clusters of serine residues in response to levels of Hh activity. Mutating the first cluster, compared to mutating the other clusters, impairs Smo activity more severely, whereas mutating the last cluster prohibits C-terminus dimerization. In addition, phosphorylation of the membrane proximal cluster promotes phosphorylation of the distal cluster. We propose a zipper-lock model in which the gradual phosphorylation at these clusters induces a gradual conformational change in the Smo cytoplasmic tail, which promotes the interaction between Smo and Costal2 (Cos2). Moreover, we show that Hh regulates both PKA and CK1 phosphorylation of Smo. Thus, the differential phosphorylation of Smo mediates the thresholds of Hh activity.


Relay and higher-order thalamic nuclei show an intertwined functional association with cortical-networks.
Almost all functional processing in the cortex strongly depends on thalamic interactions. However, in terms of functional interactions with the cerebral cortex, the human thalamus nuclei still partly constitute a terra incognita. Hence, for a deeper understanding of thalamic-cortical cooperation, it is essential to know how the different thalamic nuclei are associated with cortical networks. The present work examines network-specific connectivity and task-related topical mapping of cortical areas with the thalamus. The study finds that the relay and higher-order thalamic nuclei show an intertwined functional association with different cortical networks. In addition, the study indicates that relay-specific thalamic nuclei are not only involved with relay-specific behavior but also in higher-order functions. The study enriches our understanding of interactions between large-scale cortical networks and the thalamus, which may interest a broader audience in neuroscience and clinical research.


Transcatheter aortic valve implantation in dialysis patients.
Transcatheter aortic valve implantation (TAVI) has emerged as a new therapeutic option for high-risk patients. However, dialysis patients were excluded from all previous studies. The aim of this study is to compare the outcomes of TAVI for dialysis patients with those for patients with chronic kidney disease (CKD) stages 3 and 4 and to compare TAVI with open surgery in dialysis patients. Part I: comparison of 10 patients on chronic hemodialysis with 116 patients with non-dialysis-dependent CKD undergoing TAVI. Part II: comparison of transcatheter (n = 15) with open surgical (n = 24) aortic valve replacement in dialysis patients. Part I: dialysis patients were significantly younger (72.3 vs. 82.0 years; p < 0.01). Hospital stay was significantly longer in dialysis patients (21.8 vs. 12.1 days; p = 0.01). Overall 30-day mortality was 3.17%, with no deaths among dialysis patients. Six-month survival rates were similar (log-rank p = 0.935). Part II: patient age was comparable (66.5 vs. 69.5 years; p = 0.42). Patients in the surgical group tended to stay longer in hospital than TAVI patients (29.5 vs. 22.5 days; p = 0.35). TAVI is a safe procedure in patients on chronic hemodialysis. Until new data become available, we find no compelling reason to refuse these patients TAVI.


Genetics of human gastrointestinal sensation.
The objective was to review the genetics of human visceral pain with particular emphasis on pain associated with irritable bowel syndrome. The biomarkers most commonly employed in identifying visceral hypersensitivity are sensation ratings and thresholds or brain imaging during viscus (e.g., rectal) distension. Genetic studies suggest that variation in the control of candidate genes involved in ion channel function, neurotransmitter synthesis, reuptake or receptor functions, and inflammatory disease susceptibility loci may impact variations in prevalence of the symptom phenotype of abdominal pain or IBS, or quantitative traits (intermediate phenotypes) of rectal sensation. The candidate genes include SLC6A4, CNR1, and TNFSF15 reflecting serotonin reuptake, cannabinoid receptors, and inflammatory-barrier functions. However, other than TNFSF15, the other candidate genes are only univariately associated with pain, IBS symptom complex, or quantitative traits of sensation. These data have generated hypotheses and present opportunities for study of mechanisms and treatment of visceral pain in humans, which remains an unmet clinical need in patients with IBS and functional abdominal pain.


Comparison of long-term mortality according to obesity in patients with successful percutaneous chronic total occlusion interventions using drug-eluting stents.
To evaluate the long-term mortality according to obesity in patients with chronic total occlusion (CTO) lesions after successful percutaneous coronary intervention (PCI). Despite the potential impact of coronary revascularization and lesion severity on the obesity paradox, the long-term survival according to obesity in CTO patients after successful PCI has been unknown. Between January 2003 and September 2014, we examined 1,172 consecutive Korean patients with 1,190 CTO lesions who underwent successful drug-eluting stent (DES) implantation in two tertiary academic medical centers. The primary and secondary endpoints were all-cause and cardiac death, respectively. Obesity was defined as a body mass index ≥25.0 kg/m2 , based on the criteria for Asians. The median follow-up time was 4.4 years. The prevalence of obesity was 54.4%. During the follow-up periods, the occurrence of all-cause (6.1 vs. 10.7%) and cardiac death (3.8 vs. 6.7%) was lower in obese patients than in non-obese patients (P <0.05, respectively). Kaplan-Meier analysis showed that obese patients had lower cumulative rates of all-cause and cardiac death than did non-obese patients (log-rank P <0.05, respectively). Univariate Cox regression analysis showed that age ≥65 years (hazard ratio [HR], 3.62), diabetes mellitus (HR, 1.94), renal dysfunction (HR, 7.03), systolic heart failure (HR, 2.61), and obesity (HR, 0.58) were associated with all-cause death (P <0.05). Multivariate Cox regression models showed that high BMI was independently associated with the decreased risk of all-cause death. Obese patients appear to have a lower long-term mortality than do non-obese patients in CTO after successful PCI using DES. © 2017 Wiley Periodicals, Inc.


Identification and characterization of Hand2 upstream genomic enhancers active in developing stomach and limbs.
The bHLH transcription factor HAND2 plays important roles in the development of the embryonic heart, face, limbs, and sympathetic and enteric nervous systems. To define how and when HAND2 regulates these developmental systems, requires understanding the transcriptional regulation of Hand2. Remarkably, Hand2 is flanked by an extensive upstream gene desert containing a potentially diverse enhancer landscape. Here, we screened the regulatory interval 200 kb proximal to Hand2 for putative enhancers using evolutionary conservation and histone marks in Hand2-expressing tissues. H3K27ac signatures across embryonic tissues pointed to only two putative enhancer regions showing deep sequence conservation. Assessment of the transcriptional enhancer potential of these elements using transgenic reporter lines uncovered distinct in vivo enhancer activities in embryonic stomach and limb mesenchyme, respectively. Activity of the identified stomach enhancer was restricted to the developing antrum and showed expression within the smooth muscle and enteric neurons. Surprisingly, the activity pattern of the limb enhancer did not overlap Hand2 mRNA but consistently yielded a defined subectodermal anterior expression pattern within multiple transgenic lines. Together, these results start to uncover the diverse regulatory potential inherent to the Hand2 upstream regulatory interval.


Multiple blood transfusions reduce the recurrence rate of Crohn's disease.
In order to determine whether perioperative blood transfusion affects the recurrence of Crohn's disease, the authors reviewed the records of 79 patients with Crohn's disease who underwent their initial intestinal resection at their institution. Recurrence of Crohn's disease was documented by radiographic studies, endoscopy, or laparotomy. During the hospital admission for resection, 45 patients received multiple red blood cell transfusions. Recurrence developed in 22 percent of these patients by 36 months, and the median time to recurrence was 35 months. In the 34 patients who did not receive multiple transfusions, recurrence was found in 44 percent by 36 months, and the median time to recurrence was 20 months. These differences are significant, using the Kaplan-Meier analysis (P less than 0.04). Recurrence in patients with disease limited to the small bowel or to the colon was not significantly affected by the transfusion status. However, recurrence developed in only 10 percent of multiply transfused patients with ileocolic disease by 36 months, whereas recurrence developed in 45 percent of the patients who were not multiply transfused. (Significance, P = 0.057). The authors believe that the observed decreased rate of recurrence of Crohn's disease in patients receiving multiple perioperative transfusions may represent another example of clinically significant immunosuppression from blood transfusion.


Entropic effects of disulphide bonds on protein stability.
To measure the thermodynamic consequences of the reduction in the number of polypeptide-chain conformations that accompanies protein folding, we developed a method called loop permutation analysis. In this approach, the stabilizing contributions of three engineered disulphide bonds were compared in extended and circularly permutated mutants of phage T4 lysozyme. The observed differences in disulphide contributions, although qualitatively consistent with theoretical estimates, were not solely proportional to the differences in loop length. These findings suggest that in addition to the length of the chain, the polypeptide sequence may influence the energetic consequences of conformational restrictions.


The effects of melatonin on postoperative intraabdominal adhesion formation.
Postoperative intraabdominal adhesion formation is a major clinical problem. No previous study was found, reporting the relationship between adhesion formation and melatonin administration, but melatonin, a strong antioxidant, is recognized to have certain effects on the progression of adhesion formation mechanism. It was therefore decided to investigate the effects of melatonin on postoperative adhesion formation. A total number of 24 Sprague-Dawley rats were utilized. Three groups, described as: Group A, sham laparatomy (n=8), Group B, rats that underwent only ischemia-reperfusion (n=8) and Group C, rats that underwent ischemia- reperfusion and were given 10 mg/kg melatonin solution i.v. (n=8). For Groups B and C, the ileocolic vessels were clamped. Blood glutathione peroxidase levels of all study groups were assessed, then microscopic and macroscopic adhesion scores were evaluated. Glutathione peroxidase levels of the melatonin-treated group were significantly higher and fibroblast proliferation and macroscopic adhesion scores were significantly lower, than in the melatonin-free group. The results of this study supported the hypothesis, that melatonin administration may prevent intraabdominal adhesions resulting from surgery.


A method for estimating the effective number of loci affecting a quantitative character.
A likelihood method is introduced that jointly estimates the number of loci and the additive effect of alleles that account for the genetic variance of a normally distributed quantitative character in a randomly mating population. The method assumes that measurements of the character are available from one or both parents and an arbitrary number of full siblings. The method uses the fact, first recognized by Karl Pearson in 1904, that the variance of a character among offspring depends on both the parental phenotypes and on the number of loci. Simulations show that the method performs well provided that data from a sufficient number of families (on the order of thousands) are available. This method assumes that the loci are in Hardy-Weinberg and linkage equilibrium but does not assume anything about the linkage relationships. It performs equally well if all loci are on the same non-recombining chromosome provided they are in linkage equilibrium. The method can be adapted to take account of loci already identified as being associated with the character of interest. In that case, the method estimates the number of loci not already known to affect the character. The method applied to measurements of crown-rump length in 281 family trios in a captive colony of African green monkeys (Chlorocebus aethiopus sabaeus) estimates the number of loci to be 112 and the additive effect to be 0.26 cm. A parametric bootstrap analysis shows that a rough confidence interval has a lower bound of 14 loci.


Matrix metalloproteinase induction by EMMPRIN in experimental focal cerebral ischemia.
Focal cerebral ischemia leads to the gradual disruption of the extracellular matrix. A key role in the turnover of the extracellular matrix is played by the system of matrix metalloproteinases (MMPs). In this study we describe changes of the MMP inducer protein (EMMPRIN) following experimental cerebral ischemia (induced for 3 h and followed by 24 h reperfusion, suture model) in rats. Extracellular EMMPRIN was measured by Western blot of the ischemic and nonischemic basal ganglia and cortex separately. Compared with the contralateral nonischemic area, the ischemic hemisphere showed a significant increase in EMMPRIN: basal ganglia, 158% +/- 4% (P < 0.05); cortex, 128% +/- 25% (P < 0.05). Immunohistochemistry was used to localize EMMPRIN on cerebral microvessels. EMMPRIN-positive microvascular structures were quantified by automatic morphometric video-imaging analysis and a significant increase in the number of cerebral microvessels staining positive for EMMPRIN in the ischemic basal ganglia was shown. The significant loss of microvascular basal lamina antigen collagen type IV in ischemic cortex and basal ganglia was calculated by Western blot. Measured by gelatin zymography, we demonstrated an MMP-2 and MMP-9 increase in the ischemic brain regions (P < 0.05). For the first time the MMP activation system EMMPRIN was shown to be relevant in cerebral ischemia. These results raise the possibility that the increased expression of EMMPRIN, the increase in MMPs and the damage of the basal lamina following cerebral ischemia are connected and part of a network of related changes.


Changes of cell-vascular complex in zones of adaptive remodeling of the bone tissue under microgravity conditions.
We examined the peculiarities of the structure of the blood-vascular bed and perivascular cells in zones of osteogenesis in the epiphyses and metaphises of femoral bones of rats, flown aboard the US laboratory SLS-2 for two weeks by electron microscopy and histochemistry. In zones of bone remodeling, there was a tendency for a reduction of sinusoid capillary specific volume. Endotheliocytes preserve the typical structure. In the population of perivascular cells, we discovered differentiating osteogenic cells that contained alkaline phosphomonoesterase as well as cells that don't contain this enzyme and differentiate into fibroblasts. The fibroblasts genesis in zones of adaptive remodeling of spongy bones leads to a further development of fibrous tissue that is not subject to mineralization.


Evaluation of a proposed standard reporting system for preoperative angiograms in infrainguinal bypass procedures: angiographic correlates of measured runoff resistance.
Preoperative angiography is widely used to estimate runoff before peripheral vascular bypass surgery. The Ad Hoc Committee on Reporting Standards for the Society for Vascular Surgery and the International Society for Cardiovascular Surgery recently proposed an angiographic scoring system that grades the quality of vessels distal to the proposed bypass site and calculates an overall runoff score after adjusting each vessel score by an arbitrary weighting factor. We compared this score with intraoperatively measured runoff resistance in 67 patients undergoing infrainguinal bypass. Correlation between overall runoff score and measured resistance varied with the distal bypass site and was reasonably predictive for femoropopliteal above-knee bypasses (r = 0.67, p = 0.004, N = 17) and femoroposterior tibial bypasses (r = 0.73, p = 0.03, N = 9), but not for femoropopliteal below-knee (r = 0.05, p = 0.76, N = 34) or femoroperoneal (r = 0.57, p = 0.18, N = 7) bypasses. When multiple linear regression was used to calculate the weighting factors (rather than using arbitrarily assigned factors), the correlation between overall angiogram score and measured resistance improved substantially for femoropopliteal above-knee (r = 0.85, p = 0.00006), femoropopliteal below-knee (r = 0.50, p = 0.03) and femoroperoneal (r = 0.83, p = 0.02) bypasses. Correlation for the entire group of 67 patients improved from r = 0.30 (p = 0.02) to r = 0.64 (p = 0.0001). We conclude that the committee's scoring system correlates with measured runoff resistance but can be improved by the use of multiple linear regression to calculate weighting factors for each vessel in the outflow tract.


Kidney loss due to periureteral fibrosis and ureteral obstruction secondary to migration of subureterically injected calcium hydroxylapatite.
Vesicoureteral reflux (VUR) is one of the significant urologic diseases of childhood and its endoscopic treatment is a viable option in terms of both simplicity and reduced morbidity. However, despite intensive research, no ideal injection material that yields the best long-term results with the least side effects has been introduced as yet. Synthetic calcium hydroxylapatite is one of the materials that has recently been under trial. Although favorable short-term success rates have been reported with the subureteric injection of calcium hydroxylapatite without any side effects, this case report shows its potential to migrate. To our knowledge, we present the first case where the migration of subureterically injected calcium hydroxylapatite resulted in periureteral fibrosis, ureteric obstruction and subsequent renal loss.


Solving the Problem of Nonadherence to Immunotherapy.
Allergen immunotherapy (AIT) can improve allergic response by modifying the underlying disease. Many patients are nonadherent, and do not achieve full benefit. Numerous studies reveal that fewer than 10% of patients complete a full course and that most abandon treatment in the first year. The development and testing of interventions to improve AIT are emerging. Data from adherence interventions in other chronic conditions provide guidance to allergists/immunologists. Evidence-based communication strategies-patient-centered care, motivational interviewing, and shared-decision making-underscore the importance of taking time to establish trust, understand patient concerns and priorities, and involve the patient in decisions regarding AIT.


LDeform: Longitudinal deformation analysis for adaptive radiotherapy of lung cancer.
Conventional radiotherapy for large lung tumors is given over several weeks, during which the tumor typically regresses in a highly nonuniform and variable manner. Adaptive radiotherapy would ideally follow these shape changes, but we need an accurate method to extrapolate tumor shape changes. We propose a computationally efficient algorithm to quantitate tumor surface shape changes that makes minimal assumptions, identifies fixed points, and can be used to predict future tumor geometrical response. A novel combination of nonrigid iterative closest point (ICP) and local shape-preserving map algorithms, LDeform, is developed to enable visualization, prediction, and categorization of both diffeomorphic and nondiffeomorphic tumor deformations during an extended course of radiotherapy. We tested and validated our technique on 31 longitudinal CT/MRI subjects, with five to nine time points each. Based on this tumor deformation analysis, regions of local growth, shrinkage, and anchoring are identified and tracked across multiple time points. This categorization in turn represents a rational biomarker of local response. Results demonstrate useful predictive power, with an averaged Dice coefficient and surface mean-squared error of 0.85 and 2.8 mm, respectively, over all images. We conclude that the LDeform algorithm can facilitate the adaptive decision-making process during lung cancer radiotherapy.


The transcriptome of the human mast cell leukemia cells HMC-1.2: an approach to identify specific changes in the gene expression profile in KitD816V systemic mastocytosis.
To circumvent the costly isolation procedure associated with tissue mast cells, human mast cell lines such as HMC-1 are employed in mastocytosis research, but their relation to mutated mast cells in systemic mastocytosis has not been investigated systematically. In the present study, we determined the transcriptome of HMC-1.2 cells and compared the expression data with those reported in the literature for normal human resting lung and tonsillar mast cells as well as leukocytes from peripheral blood and mononuclear cells from bone marrow aspirates of patients with D816 V-positive systemic mastocytosis. Our results suggest that HMC-1.2 cells are an appropriate model for the investigation of this variant of systemic mast cell activation disease. The data confirm previous suggestions that the pathologically increased activity of mast cells in patients with D816 V-positive systemic mastocytosis can be deduced from the detection of mutation-related changes in the gene expression profile in leukocytes from peripheral blood and in mononuclear cells from bone marrow aspirates. Thus, mutation-related changes of the expression profile can serve as surrogates (besides clustering of mast cells, expression of CD25, and increased release of tryptase) for the presence of the mutation D816 V in tyrosine kinase Kit in patients with systemic mastocytosis according to the WHO criteria. Whether this also holds true for systemic mast cell activation disease caused by other mutations in Kit or other mast cell activity-related genes is a subject for future studies.


An evaluation of undergraduate family care programs.
Evaluation of the many new family care programs (FCP), and others of similar intent, however defined, is as essential as determining the value of any other curriculum change. Replies to a questionnaire from 101 U.S. and 15 Canadian medical schools indicated that 80% of the former and 93% of the latter had FCPs; 35% and 29%, respectively, were not evaluating their program by any method. No single evaluative technique was used by more than 42% of the American medical schools. A review of the literature on FCPs frequently indicated that the conclusions that could be drawn about the programs were ambiguous. Students in the University of Cincinnati Medical Center FCPs elected family practice or pediatric internships significantly more often than did the FCP nonparticipants, but they indicated that the program had little effect on this choice, despite almost uniformly favorable testimonials. We discuss the possibility that FCPs may be educating the wrong students, that FCPs, if not reinforced in other clinical areas, may have few lasting effects on student attitudes or career choice, and that we may be asking the wrong questions, and with inadequate methods.


Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT).
Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers. The retrospective cohort analysis included 213 family members participating in the European Nicotinamide Diabetes Intervention Trial. All were aged <25 years, with at least one islet antibody in addition to ICA >or=20 Juvenile Diabetes Foundation units. Median length of follow-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox regression analysis The overall cumulative risk of diabetes within 5 years was 54.1% (95% CI 46.0-62.3). Multivariate analysis confirmed that baseline first-phase insulin response (FPIR) quartile (P < 0.0001), number of additional antibody markers (P < 0.0001), and 120-min glucose in the oral glucose tolerance test (P < 0.0001) were independent determinants of risk of progression, whereas addition of homeostasis model assessment of insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0.025) but not in those with preserved FPIR (P = 0.3). These data suggest that insulin resistance accelerates progression to type 1 diabetes in antibody-positive relatives in whom insulin secretion is markedly reduced but does not affect progression when insulin secretion is relatively well preserved.


General and COVID19-specific emotional stress: Religious practice as a potential coping strategy.
Using Spanish microdata from the Survey on mental health during the COVID-19 pandemic conducted in February 2021 by the Centre for Sociological Research (CIS), this paper aims at identifying individual factors associated with an increased risk of mental or emotional distress arising from two different sources: a general pattern of depression or anxiety and distress specifically associated with the pandemic as measured by fears and worries about one's own or others' lives and job and income insecurity due to the COVID-19 health crisis. We explore gender differences in both types of mental distress as well as the role of individual religiosity, measured as religious beliefs and behaviours, as a potential coping strategy. In both general and COVID-specific mental distress, our results provide evidence of gender differences in the risk of suffering these conditions, with a higher incidence among women. We also find that religious beliefs and practice seem to have served as a coping strategy that has allowed females to narrow the gender gap, particularly for practising Catholics. The evidence is stronger for mental distress associated with anxiety or depression. However, it is still present, albeit to a lesser extent, for suffering caused by pandemic-related mental stressors. Our results suggest that religious practices and beliefs might play a key role in alleviating additional distress symptoms caused by emergency situations such as those suffered during the COVID-19 pandemic.


Promoter polymorphism influences the effect of dexamethasone on transcriptional activation of the LTC4 synthase gene.
The molecular mechanisms of corticosteroid action in asthma are gradually being elucidated. The LTC4S gene encodes for LTC(4) synthase, the terminal enzyme in the generation of cysteinyl-leukotrienes (cys-LTs), which are key mediators in the pathogenesis of asthma. We have identified a novel promoter polymorphism in LTC4S at position -1072 (G/A) and a -444 (A/C) polymorphism has previously been reported. We hypothesised that the LTC4S gene promoter may be a potential site of regulation by corticosteroids and that genetic polymorphism may determine their effects at this locus. Using in vitro transfection of promoter-reporter constructs, dexamethasone was shown to increase transcription of LTC4S by more than 50% for the -1072G/-444A, A-C and G-C haplotype constructs (P&<0.02), but to have no effect on the A-A haplotype (P=0.27). These data identify an interesting phenomenon that requires validation in a human study examining ex vivo production of LTC(4) in cells from genotyped asthmatic and nonasthmatic subjects. The 9% of the Caucasian asthmatic population with the A-A haplotype may have genetically predetermined lower cys-LT levels in the presence of corticosteroids compared to other patients. These findings have potential implications in the evaluation of combined corticosteroid and antileukotriene therapy in asthma.


Studies on the nephrotoxicity of p-nitrophenylarsonic acid: changes in rat kidney and urinary enzyme activities following the administration of p-nitrophenylarsonic acid.
Histological studies showed that the administration of p-nitrophenylarsonic acid to rats resulted in renal tubular necrosis. The nephrotoxin was administered intraperitoneally and doses greater than 30 mg/kg were found to be fatal. The severity of the renal lesion depended on the amount of the nephrotoxin used. Elevated serum urea levels, urinary protein and volume were recorded over an 8-day period following the injection of the nephrotoxin. These changes were paralleled by an increase in the activity of lactate dehydrogenase, acid and alkaline phosphatase, N-acetyl-beta-glucosaminidase and beta-glucosidase in the urine. beta-Glycosidase activities increased in kidney homogenates, immediately after the injection of the nephrotoxin, but this eventually fell to well below the normal range. Subcellular fractions were prepared from sucrose homogenates by differential centrifugation and beta-glycosidases and cytochrome oxidase were used as enzyme markers. Only minor changes in the activity of cytochrome oxidase activity resulted from the administration of p-nitrophenylarsonic acid. One of the earliest indications of renal damage was a decrease in lysosomal latency. The activities of the lysosomal and soluble enzymes were elevated above normal during the first two days after the injection of p-nitrophenylarsonic acid, but they fell to values, significantly lower than normal, on the third day. The isoenzymic forms of beta-galactosidase, beta-glucosidase and N-acetyl-beta-glucosaminidase in normal and damaged kidneys were studied, using starch gel electrophoresis. The activities of both the lysosomal and the soluble forms of these enzymes decreased following the injection of the nephrotoxin, confirming the results obtained with whole homogenates. The relationship between the changes in renal enzyme activity and urinary enzyme excretion during the nephrotoxic process is discussed.


Isotope effects in self-organization of internal transport barrier and concomitant edge confinement degradation in steady-state LHD plasmas.
The isotope effect, which has been a long-standing mystery in the turbulent magnetically confined plasmas, is the phenomena that the plasma generated with heavier hydrogen isotope show a mitigated transport. This is on the contrary to what is predicted with the simple scaling theory, in which the heavier ions easily diffuse because of its larger gyro-radius. Thanks to the newly developed analysis method and a comprehensive parameter scan experiment in the steady-state plasmas in the Large Helical Device (LHD), the isotope effect was clearly observed in the self-organized internal transport barrier (ITB) structure for the first time. Comparing the ITB intensity in deuterium (D) and hydrogen (H) plasmas, two distinct hydrogen isotope effects are found: stronger ITB is formed in D plasmas and a significant edge confinement degradation accompanied by the ITB formation emerges in H plasmas. This observation sheds light on a new aspect of the turbulent plasmas regarding how the basic properties of the fluid material affect the turbulent structure formation in the open-system.


Neurology International Expands Its' Scope and Mission: Exploring the Nervous System in Health and Disease with Emphasis on Molecular and Pathologic Aspects.
Having served as editor-in-chief for Neurology International since its inception back in 2009, I am very pleased to see the journal grow and expand, with a major development now taking place with new ownership by MDPI, a world leader in Open Access Journal publication [...].


Study of rosin-glycerol esters as microencapsulating materials. II. Quantitative correlation between physico-chemical properties and release characteristics.
Rosin-glycerol esters have been used as microencapsulating materials. A quantitative correlation has been observed between the physico-chemical properties, i.e. acid value and moisture affinity, and the release characteristics from the encapsulated drug.


Risk factors for mortality caused by hypothalamic obesity in children with hypothalamic tumours.
Hypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation. To identify predictive factors for mortality caused by HyOb in children. Twenty children with HyOb secondary to hypothalamic tumours that were followed-up for ≥3 years and aged <15 years at diagnosis, and received supraphysiological glucocorticoid treatment for ≤1 month. Mean age at diagnosis was 6.36 ± 3.60 years. Mean body mass index (BMI) Standard deviation of the samples (SDS) increased from 0.77 ± 1.26 to 2.66 ± 1.45 during the first 6 months, but slowed from month 6-12 (2.73 ± 1.35). ΔBMI SDS at 0-6 months was significantly higher in patients aged <6 years at diagnosis than in those aged >6 years at diagnosis (3.71 ± 1.96 vs. 0.83 ± 0.73, P < 0.001). Maximum BMI SDS was also significantly higher in the younger group (3.88 ± 1.39 vs. 2.79 ± 0.64, P < 0.05). In all, four patients died and the mortality rate was significantly higher in the patients with a further increase in BMI SDS > 1 SDS after 6 months of therapy (RR: 8.4, P < 0.05). Both overall mortality and obesity-related mortality rates were higher in the patients aged <6 years at diagnosis (4.5-fold, 7.2-fold higher, respectively, P > 0.05). The mortality rate was also 3.7-fold higher in the patients with a maximum BMI SDS ≥ 3 at any time during the first 3 years after therapy(P > 0.05). An increase in BMI SDS after 6 months of therapy was observed to be a risk factor for mortality caused by HyOb. In addition, age <6 years at diagnosis and a maximum BMI SDS ≥ 3 were associated with a higher mortality rate, indicating that earlier and more aggressive treatment of obesity is required.


Expression of mouse Amy-2a alpha-amylase genes is regulated by strong pancreas-specific promoters.
Three types of Amy-2-related DNA sequences, Amy-2a I, Amy-2a II and Amy-X, exist in the genome of mice of the inbred strain A/J. Amy-2a I and Amy-X are single copy sequences. Amy-2a II occurs as three copies per haploid genome. DNA sequence analysis reveals that both classes of Amy-2a genes specify the same unique pancreatic alpha-amylase mRNA species, since they share common exon sequences. Four independently cloned Amy-2a II isolates were found to be identical in all regions sequenced. This suggests that most, if not all, chromosomal Amy-2a II copies are identical. Amy-X is presumably a pseudogene, since its exon sequences, which are distinct from those of Amy-2a, are not detected in pancreatic alpha-amylase mRNA. We have determined the transcriptional activities of the Amy-2a genes by mapping in vitro elongated nascent transcripts to Amy-2a restriction fragments. Transcription initiation occurs at or close to the cap site. The expression of Amy-2a in vivo is under control of strong promoters, which are active exclusively in the pancreas. The accumulation of alpha-amylase mRNA in cells of the exocrine pancreas is regulated mainly at the transcriptional level. We have searched for pancreatic transcripts of Amy-1a, which specifies both parotid gland and liver-type alpha-amylase mRNAs. Surprisingly, the weak Amy-1a promoter, which directs the synthesis of the mRNA containing the liver-type leader sequence, also is active in the pancreas and, hence, in all alpha-amylase-producing tissues.