Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep.
To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(-) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling. 8 female Dorset crossbred sheep. A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP [3 mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg, IV),and R(-) KTP (1.5 mg/kg, IV). Both KTP enantiomers had elimination half-life and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(-) KTP Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP, but not R(-) KTP, also significantly inhibited PGE2 synthesis in exudate for 12 hours. Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.


[Role of different fractions of adhering splenocytes in inducing antibody formation in irradiated mice].
Adhering splenic cells were separated into the following fractions by centrifugation in the Ficoll density gradient: A (12--16% of Ficoll in the interphase), B (16--21%), C (21--25%) and D (in the sediment). The influence of the cells in fractions B, C and D on the immune response to sheep red blood cells was studied in vivo (in sublethally irradiated mice). When injected simultaneously with lymphocytes, the splenic cells in fractions B and C significantly increased the number of antibody-producing cells in the recipient's spleen. Without lymphocytes neither the initial population of adhering splenic cells, nor its fractions induced the production of antibodies.


Mental health professionals' perspectives on the implementation of smoke-free policies in psychiatric units across England.
The original audit on which this 2013 secondary analysis is based, was conducted in 2010. It explored implementation of smoke-free policies from the perspective of unit managers in 147 psychiatric units across England comprising a randomly selected sample of nine different unit types. Two main themes are presented: positive perspectives of smoke-free policy implementation, and barriers and problems with smoke-free policy implementation. Analysis of unit managers' experiences and perspectives found that 96% of participants thought smoke-free policy had achieved positive outcomes for staff, patients, services and care. Consistency of response was the most prominent factor associated with policy success. Quality of the physical environment and care delivery were clear positive outcomes which enabled the environment to be more conducive to supporting staffs' and patients' quit attempts. Lack of consistency and a prevailing culture of acceptance of smoking were identified as some of the most reported perceived continuing problems. Solutions included the need to acknowledge that this type of complex systems change takes time and ongoing staff education and training. Our results demonstrate the importance of taking into account the experiences and attitudes of staff responsible for enacting smoke-free policy.


Evidence for genetic linkage between the ure and trh genes in Vibrio parahaemolyticus.
Although V. parahaemolyticus does not generally produce urease, several studies have reported urease-positive V. parahaemolyticus isolates from clinical sources. Recently, studies have shown a complete coincidence between the urease-producing phenotype of V. parahaemolyticus strains and the possession of the thermostable direct haemolysin (TDH)-related haemolysin (TRH) gene (trh). TRH, like TDH, is considered to be an important virulence factor in the pathogenesis of V. parahaemolyticus gastroenteritis. The present study attempted to identify the gene ure encoding urease in V. parahaemolyticus to clarify the relationship between urease production and possession of trh. The polymerase chain reaction with mixed oligonucleotide primers targeted for conserved sequences of reported ure genes from other species was used to prepare a DNA probe to detect the V. parahaemolyticus ure gene. Colony hybridisation with this ure probe demonstrated that all the ure-positive strains produced urease. Considering the coincidence between production of urease and possession of trh in V. parahaemolyticus, it was concluded that the presence or absence of the ure gene is completely coincident with that of the trh gene in V. parahaemolyticus strains. Furthermore, the relative location of ure and trh on V. parahaemolyticus chromosomal DNA was analysed by pulsed-field gel electrophoresis. The results showed that, in all the strains examined, ure and trh were detected on the same NotI fragment, showing that the two genes localise within a relatively small portion of the chromosome DNA. These results suggest that the ure and trh genes are genetically linked in V. parahaemolyticus strains.


Discrete molecular dynamics can predict helical prestructured motifs in disordered proteins.
Intrinsically disordered proteins (IDPs) lack a stable tertiary structure, but their short binding regions termed Pre-Structured Motifs (PreSMo) can form transient secondary structure elements in solution. Although disordered proteins are crucial in many biological processes and designing strategies to modulate their function is highly important, both experimental and computational tools to describe their conformational ensembles and the initial steps of folding are sparse. Here we report that discrete molecular dynamics (DMD) simulations combined with replica exchange (RX) method efficiently samples the conformational space and detects regions populating α-helical conformational states in disordered protein regions. While the available computational methods predict secondary structural propensities in IDPs based on the observation of protein-protein interactions, our ab initio method rests on physical principles of protein folding and dynamics. We show that RX-DMD predicts α-PreSMos with high confidence confirmed by comparison to experimental NMR data. Moreover, the method also can dissect α-PreSMos in close vicinity to each other and indicate helix stability. Importantly, simulations with disordered regions forming helices in X-ray structures of complexes indicate that a preformed helix is frequently the binding element itself, while in other cases it may have a role in initiating the binding process. Our results indicate that RX-DMD provides a breakthrough in the structural and dynamical characterization of disordered proteins by generating the structural ensembles of IDPs even when experimental data are not available.


A macular hole in a female adult with bilateral coats disease.
To report a case of a macular hole in a female adult with bilateral Coats disease. The fundus photograph, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed in two eyes, and observed theirs characters. Fundus photograph showed massive yellowish-white exudation in the temporal midperiphery of both eyes, but the degree was slighter in the right eye. There was 1/3 DD macular hole in left eye. FFA revealed general dilatation of capillaries, multiple aneurysms, and tortuous and closure of vessels in superotemporal midperiphery in both eyes, but the degree was slighter in the right eye. There was a one-third DD round transmitted fluorescence according the macula hole. ICGA revealed that hyperfluorescence of aneurysms in superotemporal midperiphery, the images of aneurysms were more clearly than in FFA. There was a 2/3 DD hypoflurescence of macula in the late phase of angiography. FFA and ICGA have respective advantage in revealing vascular abnormalities of Coats disease. Maybe there was some relationship between the abnormalities of retinal vascular and hypoperfusion of choroidial vascular in macula in this case.


Further reductions in nonvertebral fracture rate with long-term denosumab treatment in the FREEDOM open-label extension and influence of hip bone mineral density after 3 years.
Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis. This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates. Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n = 2,343 long-term; n = 1,731 cross-over) who enrolled in the extension, missed ≤1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated. For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR] = 0.64; 95 % confidence interval (CI) = 0.48 to 0.85, p = 0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR = 0.79; 95 % CI = 0.62 to 1.00, p = 0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD). Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.


Effect of disturbance on assemblages: an example using porifera.
Extensive sponge assemblages are found in a number of habitats at Lough Hyne Marine Nature Reserve. These habitats are unusual in experiencing a range of environmental conditions, even though they are only separated by small geographic distances (1-500 m), reducing the possibility of confounding effects between study sites (e.g., silica concentrations and temperature). Sponge assemblages were examined on ephemeral (rocks), stable (cliffs), and artificial (slate panels) hard substrata from high- and low-energy environments that were used to represent two measures of disturbance (flow rate and habitat stability). Sponge assemblages varied considerably between habitat types such that only 26% (25 species) of species reported were common to both rock and cliff habitats. Seven species (of a total of 96 species) were found in the least-developed assemblages (slate panels) and were common to all habitats. Sponge assemblages on rocks and panels varied little between high- and low-energy environments, whereas assemblages inhabiting cliffs varied considerably. Assemblage composition was visualized using Bray-Curtis similarity analysis and Multi-Dimensional Scaling, which enabled differences and similarities between sponge assemblages to be visualized. Cliffs from high- and low-energy sites had different assemblage compositions compared to large rocks, small rocks, and panels, all of which had similar assemblages irrespective of environmental conditions. Differences in assemblages were partially attributed to sponge morphology (shape), as certain morphologies (e.g., arborescent species) were excluded from 2-D rock habitats. Other mechanisms were also considered responsible for the sponge assemblages associated with different habitats.


Combinatorial incorporation of enhancer-blocking components of the chicken beta-globin 5'HS4 and human T-cell receptor alpha/delta BEAD-1 insulators in self-inactivating retroviral vectors reduces their genotoxic potential.
Insertional mutagenesis by retroviral vectors has emerged as a serious impediment to the widespread application of hematopoietic stem cell gene transfer for the treatment of hematologic diseases. Here we report the development of a 77-base pair element, FII/BEAD-A (FB), which contains the minimal enhancer-blocking components of the chicken beta-globin 5'HS4 insulator and a homologous region from the human T-cell receptor alpha/delta BEAD-1 insulator. With a new flow cytometry-based assay, we show that the FB element is as effective in enhancer-blocking activity as the prototypical 1.2-kilobase 5'HS4 insulator fragment. When incorporated into the residual U3 region of the 3' long terminal repeat (LTR) of a self-inactivating (SIN) gammaretroviral vector, the FB element was stably transferred to the 5' LTR during reverse transcription, flanking the integrated transgene expression cassette. Notably, using a recently established in vitro insertional mutagenesis assay involving primary murine hematopoietic cells, we found that SIN gammaretroviral vectors, as well as SIN lentiviral vectors, containing the FB element exhibited greatly reduced transforming potential-to background levels under the experimental conditions used-compared with their unshielded counterparts. These results suggest that the FB element-mediated enhancer-blocking modification is a promising approach to dramatically improve the safety of retroviral vectors for therapeutic gene transfer.


High performance liquid chromatography-tandem mass spectrometric assay of dexmedetomidine in plasma, urine and amniotic fluid samples for pregnant ewe model.
Dexmedetomidine (DEX; Precedex(®)), approved by the Food and Drug Administration (FDA) in 1999 as a sedative for use in the intensive care unit, is a potent and highly selective α2-adrenoceptor agonist with significant sedative, analgesic and anxiolytic effects. However, the research of DEX use during pregnancy is limited and the impact of DEX on the fetal development is unclear. This article describes a high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay suitable for various biomatrices of plasma, urine and amniotic fluid, as a prerequisite for pharmacokinetic characterization of DEX in the pregnant ewe model. DEX and testosterone (internal standard; IS) were extracted from 200μL of plasma, urine or amniotic fluid with ethyl acetate. The HPLC resolution was achieved on an Agilent ZORBAX SB-CN column with a gradient elution at a flow rate of 0.5mL/min using a mobile phase of 5-100% of acetonitrile with 0.5% formic acid (mobile phase B) in water (mobile phase A). The detection was performed by a triple quadrupole tandem mass spectrometer with positive electrospray ionization. The precursor/product transitions (m/z) in the positive ion mode [M+H](+) were m/z 201.5→95.4 for DEX and m/z 289.2→109.1 for IS. The method was validated in the concentration range of 25 (lower limit of quantification; LLOQ)-5000pg/mL for both maternal and fetal plasma, and of 50 (LLOQ)-5000pg/mL for urine and amniotic fluid, respectively. The intra- and inter-day precision and accuracy were within ±9%. The overall recoveries of DEX were 82.9-87.2%, 85.7-88.4%, 86.2-89.7% and 83.7-88.1% for maternal plasma, urine, fetal plasma and amniotic fluid, respectively. The percentage matrix factors in different biomatrices were less than 120%. Stability studies demonstrated that DEX was stable after three freeze/thaw cycles, in the autosampler tray at 20°C for 24h and during the 3h sample preparation at room temperature. The validated HPLC-MS/MS method has been successfully employed for pharmacokinetic evaluation of DEX in pregnant ewes and fetuses.


Cytoreductive Surgery for Metastatic Gastrointestinal Stromal Tumors Treated With Tyrosine Kinase Inhibitors: A 2-institutional Analysis.
To refine treatment recommendations for patients with metastatic gastrointestinal stromal tumors (GISTs) treated with tyrosine kinase inhibitors (TKIs) and surgery. Early reports suggested that patients with metastatic GIST responding to TKIs treated with surgery may have favorable outcomes. However, identification of prognostic factors was limited by small cohorts. Progression-free survival (PFS) and overall survival (OS) from time of surgery and from start of initial TKI was determined. Multivariate analysis was conducted on all patients undergoing GIST metastasectomy between 2001 and 2014 at 2 institutions. We performed 400 operations on 323 patients with metastatic GIST on TKIs. Radiographic response at time of surgery was classified as responsive disease (RD, n = 64, 16%), stable disease (SD, n = 100, 25%), unifocal progressive disease (UPD, n = 132, 33%), and multifocal progressive disease (MPD, n = 104, 26%). For patients on imatinib before surgery, radiographic response was predictive of PFS from time of surgery (RD 36 months, SD 30 months, UPD 11 months, MPD 6 months; P < 0.001) and from imatinib initiation (RD 71 months, SD 51 months, UPD 47 months, MPD 33 months; P < 0.001). Radiographic response was predictive of OS from time of surgery (RD not reached, SD 110 months, UPD 59 months, MPD 24 months; P < 0.001), and from imatinib initiation (RD not reached, SD 144 months, UPD 105 months, MPD 66 months; P = 0.005). Radiographic response was not predictive of PFS/OS for patients on sunitinib. Metastatic mitotic index ≥5/50 HPF, MPD, and R2 resection were prognostic of worse PFS/OS; primary mutation was not. Surgery in metastatic GIST patients in the absence of MPD on imatinib is associated with outcomes at least comparable with second-line sunitinib and may be considered in select patients.


The changing role of the healthcare assistant.
This article analyses the changes made to the role of the healthcare assistant (HCA) in the British healthcare system and identifies when and why these changes occurred. The main influences on the role of HCAs, from the time of Florence Nightingale through to the present day, are discussed. The role of the HCA has progressed from being an undervalued 'dead-end' job, to a skilled role that is recognised nationwide. However, the future of the HCA role is uncertain.


Strategic framework for education and training in Quality by Design (QbD) and process analytical technology (PAT).
The regulatory and technical landscape of the pharmaceutical field is rapidly evolving from one focused predominantly on development of small molecules, using well established manufacturing technologies towards an environment in which biologicals and complex modalities are being developed using advanced science and technology coupled with the application of modern Quality by Design (QbD) principles. In order that Europe keeps pace with these changes and sustains its position as major player in the development and commercialization of medicines, it is essential that measures are put in place to maintain a highly skilled workforce. A number of challenges however exist to equipping academic, industrial and health agency staff with the requisite knowledge, skills and experience to develop the next generation of medicines. In this regard, the EUFEPS QbD and PAT Sciences Network has proposed a structured framework for education, training and continued professional development, which comprises a number of pillars covering the fundamental principles of modern pharmaceutical development including the underpinning aspects of science, engineering and technology innovation. The framework is not prescriptive and is not aimed at describing specific course content in detail. It should however be used as a point of reference for those institutions delivering pharmaceutical based educational courses, to ensure that the necessary skills, knowledge and experience for successful pharmaceutical development are maintained. A positive start has been made and a number of examples of formal higher education courses and short training programs containing elements of this framework have been described. The ultimate vision for this framework however, is to see widespread adoption and proliferation of this curriculum with it forming the backbone of QbD and PAT science based skills development.


Visual reaction time and size constancy.
We carried out six experiments to find out whether simple manual reaction time (RT) to flux-equated visual stimuli of different size is modulated by size constancy or by the retinal angle subtended by the stimuli. We found that RT decreased with the increase in perceived stimulus size rather than retinal angle and that this relationship depended on the use of familiar 3-D-like stimuli and on the availability of other size-constancy cues. Thus, a stereotyped speeded motor response, such as that employed in a simple RT paradigm, is modulated by size constancy, as is the case with perceptual judgments. The present results provide original evidence on the relationship between simple RT and perception.


Evaluation of platelet activation in canine immune-mediated haemolytic anaemia.
To establish whether heightened platelet activation is a common feature of canine immune-mediated haemolytic anaemia, and to evaluate the hypothesis that platelet activation plays a role in the pathogenesis of thromboembolism. Using whole-blood flow-cytometric analysis, the proportion of activated platelets and platelet-leucocyte aggregates in blood samples from 14 dogs with immune-mediated haemolytic anaemia and 14 healthy dogs was calculated. General linear models with binomial errors were used to compare groups. Results from the immune-mediated haemolytic anaemia-affected dogs were then correlated with established risk factors for thromboembolism in canine immune-mediated haemolytic anaemia, D-dimer concentration and antithrombin activity. There was a strong correlation between platelet activation and severe thrombocytopenia, with heightened platelet activation being observed predominantly in severely thrombocytopenic dogs. Dogs with immune-mediated haemolytic anaemia, particularly those with concurrent severe thrombocytopenia, are likely to have heightened platelet activation, which may play a role in the pathogenesis of thromboembolism.


Apolipoprotein E genotype and major depression in a community of older adults. The Cache County Study.
The role of allelic variation in APOE, the genetic locus for apolipoprotein E, in geriatric depression is poorly understood. There are conflicting reports as to an association between the epsilon4 allele and depression in late life. Using a community based study of non-demented elders in Cache County, Utah, that included many very old individuals, we examined the relationship between APOE and late-onset (age > 60) depression, with particular attention to possible age effects. There was no overall association between APOE and depression. However, there was a significant interaction effect of APOE and age such that the relationship of late-onset depression with respect to presence of the epsilon4 allele was larger among those 80 and older compared with those below age 80. Consistent with previous studies, women were more likely to experience late-onset depression than men. Because we excluded prevalent cases of dementia, this pattern of relative risk with age may reflect the appearance of depressive symptoms as a prodrome of Alzheimer's disease or vascular dementia. Longitudinal studies should help to confirm or refute this explanation of the data.


Episodic syncope caused by ventricular flutter in a tiger (Panthera tigris).
A captive, 9-yr-old castrated male tiger (Panthera tigris) from an exotic cat sanctuary and rescue facility was observed to have three collapsing episodes within a 2-wk interval prior to being examined by veterinarians. No improvement in clinical signs was noted after empiric treatment with phenobarbital. During a more complete workup for epilepsy, ventricular flutter was observed on electrocardiogram (ECG). The arrhythmia resolved with a single intravenous bolus of lidocaine. Cardiac structure and function were unremarkable on echocardiogram and cardiac troponin I levels were within normal limits for domestic felids. No significant abnormalities were noted on abdominal ultrasound. Complete blood count and biochemistry panel were unremarkable, and heartworm antigen and Blastomyces urine antigen enzyme-linked immunosorbent assays were negative. Antiarrhythmic treatment with sotalol was initiated. On follow-up ECG performed 1 mo later, no significant arrhythmias were noted, and clinical signs have completely resolved.


Human VAP-C negatively regulates hepatitis C virus propagation.
Human vesicle-associated membrane protein-associated protein (VAP) subtype A (VAP-A) and subtype B (VAP-B) are involved in the regulation of membrane trafficking, lipid transport and metabolism, and the unfolded protein response. VAP-A and VAP-B consist of the major sperm protein (MSP) domain, the coiled-coil motif, and the C-terminal transmembrane anchor and form homo- and heterodimers through the transmembrane domain. VAP-A and VAP-B interact with NS5B and NS5A of hepatitis C virus (HCV) through the MSP domain and the coiled-coil motif, respectively, and participate in the replication of HCV. VAP-C is a splicing variant of VAP-B consisting of the N-terminal half of the MSP domain of VAP-B followed by the subtype-specific frameshift sequences, and its biological function has not been well characterized. In this study, we have examined the biological functions of VAP-C in the propagation of HCV. VAP-C interacted with NS5B but not with VAP-A, VAP-B, or NS5A in immunoprecipitation analyses, and the expression of VAP-C inhibited the interaction of NS5B with VAP-A or VAP-B. Overexpression of VAP-C impaired the RNA replication of the HCV replicon and the propagation of the HCV JFH1 strain, whereas overexpression of VAP-A and VAP-B enhanced the replication. Furthermore, the expression of VAP-C was observed in various tissues, whereas it was barely detected in the liver. These results suggest that VAP-C acts as a negative regulator of HCV propagation and that the expression of VAP-C may participate in the determination of tissue tropism of HCV propagation.


GABAergic mechanism mediated via D receptors in the rat periaqueductal gray participates in the micturition reflex: an in vivo microdialysis study.
The periaqueductal gray (PAG) is critically involved in the micturition reflex, but little is known about the neuronal mechanisms involved. The present study elucidated dynamic changes in dopamine (DA), glutamate and gamma-aminobutyric acid (GABA) in the rat PAG during the micturition reflex, with a focus on dopaminergic modulation using in vivo microdialysis combined with cystometrography. Extracellular levels of DA and glutamate increased, whereas levels of GABA decreased, in parallel with the micturition reflex. Application of a D(1) receptor antagonist into the PAG produced increases in maximal voiding pressure (MVP) and decreases in intercontraction interval (ICI), suggesting that the micturition reflex was facilitated by D(1) receptor blockade. The D(1) receptor antagonist prevented micturition-induced decreases in GABA efflux but had no effect on DA or glutamate. Neither a D(2) receptor antagonist nor a D(1)/D(2) receptor agonist affected these neurochemical and physiological parameters. Micturition-induced inhibition of GABA was not observed in 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of Parkinson's disease. 6-OHDA-lesioned rats exhibited bladder hyperactivity evaluated by increases in MVP and decreases in ICI, mimicking facilitation of the micturition reflex induced by D(1) receptor blockade. These findings suggest that the micturition reflex is under tonic dopaminergic regulation through D(1) receptors, in which a GABAergic mechanism is involved. Bladder hyperactivity observed in 6-OHDA-lesioned rats may be caused by dysfunction of GABAergic regulation underlying the micturition reflex. The present findings contribute to our understanding not only of the neurophysiology of the micturition reflex but also of the pathophysiology of lower urinary tract dysfunction in patients with Parkinson's disease.


Blood coagulation and fibrinolysis in male patients with hypogonadotropic hypogonadism: plasma factor V and factor X activities increase in hypogonadotropic hypogonadism.
In men, androgens have both pro- and anti-thrombotic effects. Androgen deficiency in men is associated with an increased incidence of cardiovascular disease (CVD). However, the influence of hypogonadism on hemostasis is controversial. Little is known about hemostatic features of male patients with idiopathic hypogonadotropic hypogonadism (IHH). Thus, the aim of the present study was to evaluate the markers of endogenous coagulation and fibrinolysis, and to investigate the relationships between endogenous sex hormones and hemostatic parameters and serum lipid profile in men with IHH. Seventeen patients with IHH and 20 age-matched healthy controls were included in the study. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors (F) V, VII, VIII, IX, and X activities, von Willebrand factor (vWF), antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA), and tissue plasminogen activator inhibitor (PAI-1), as well as common lipid variables, were measured. The relationships between serum sex hormones and these hemostatic parameters were examined. Compared with the control subjects, platelet count, FV, FX, and protein C activities were significantly increased in patients with IHH (p<0.01, p<0.05, p<0.01, and p<0.05, respectively), whereas AT III was decreased (p<0.05). Fibrinogen, FVIII, vWF, t-PA, PAI-1, and the other coagulation/fibrinolysis parameters and lipid profile in patients with IHH were not different from the controls. In patients with IHH, we showed that serum LH level was negatively correlated with fibrinogen (r: -0.78, p<0.01) and protein C (r: -0.55, p<0.05) and positively correlated with t-PA (r: 0.53, p<0.05). Serum FSH levels inversely correlated with fibrinogen (r: -0.75, p<0.01). We found some differences in the hemostatic parameters between the patients with IHH and healthy controls. Increased platelet count, FV and FX activities and decreased AT III levels in patients with IHH represent a potential hypercoagulable state, which might augment the risk for atherosclerotic and atherothrombotic complications. Therefore, IHH may be associated with an increased risk of CVD. However, sex hormones may play a role at different levels of the complex hemostatic system in patients with IHH.


A novel SH3-containing human gene family preferentially expressed in the central nervous system.
The Src-homology-3 domain (SH3) is an evolutionarily conserved, 50- to 60-amino-acid module carried by intracellular proteins involved in the transduction of signals for cell polarization, motility, enzymatic activation, and transcriptional regulation. The SH3 drives protein-protein interactions through binding to proline-rich ligands. This function relies on the conserved secondary structure, whereas the SH3 primary structure is highly diverse. Taking advantage of the fact that the few conserved amino acids are clustered near the N- and C-terminal ends, we designed degenerate oligonucleotides spanning these two regions and screened by PCR a variety of normal and tumor tissues for the expression of SH3-containing transcripts. Using this strategy, we have identified a novel SH3-containing human gene family of six related transcripts that map to four different chromosomes. The SH3 domain lies at the C-terminal end and shows 56-50% amino acid homology to the C-terminal SH3 of Sem-5/Drk/GRB2. The N-terminal segment of this novel SH3GL (from SH3-containing Grb2-like) gene family does not resemble any known protein. Three of these transcripts are in-frame and show a peculiar tissue distribution: SH3GL2 is preferentially expressed in the brain, SH3GL3 in brain and testis, and SH3GL1 is ubiquitous.


Regulation of rat Na(+)-K(+)-ATPase activity by PKC is modulated by state of phosphorylation of Ser-943 by PKA.
We have previously shown that the rat Na(+)-K(+)-ATPase alpha 1-isoform is phosphorylated at Ser-943 by protein kinase A (PKA) and at Ser-23 by protein kinase C (PKC), which in both cases results in inhibition of enzyme activity. We now present evidence that suggests that the phosphorylation of Ser-943 by PKA modulates the response of Na(+)-K(+)-ATPase to PKC. Rat Na(+)-K(+)-ATPase alpha 1 or a mutant in which Ser-943 was changed to Ala-943 was stably expressed in COS cells. The inhibition of enzyme activity measured in response to treatment with the phorbol ester, phorbol 12,13-dibutyrate (PDBu; 10(-6) M), was significantly reduced in the cells expressing the Ala-943 mutant compared with that observed in cells expressing wild-type enzyme. In contrast, for cells expressing Na(+)-K(+)-ATPase alpha 1 in which Ser-943 was mutated to Asp-943, the effect of PDBu was slightly enhanced. The PDBu-induced inhibition was not mediated by activation of the adenosine 3',5'-cyclic monophosphate/PKA system and was not achieved via direct phosphorylation of Ser-943. Sp-5,6-DCI-cBIMPS, a specific PKA activator, increased the phosphorylation of Ser-943, and this was associated with an enhanced response to PDBu. Thus the effect of PKC on rat Na(+)-K(+)-ATPase alpha 1 is determined not only by the activity of PKC but also by the state of phosphorylation of Ser-943.


A simple fixed-point approach to invert a deformation field.
Inversion of deformation fields is applied frequently to map images, dose, and contours between the reference frame and the study frame. A prevailing approach that takes the negative of the forward deformation as the inverse deformation is oversimplified and can cause large errors for large deformations or deformations that are composites of several deformations. Other approaches, including Newton's method and scatter data interpolation, either require the first derivative or are very inefficient. Here we propose an iterative approach that is easy to implement, converges quickly to the inverse when it does, and works for a majority of cases in practice. Our approach is rooted in fixed-point theory. We build a sequence to approximate the inverse deformation through iterative evaluation of the forward deformation. A sufficient but not necessary convergence condition (Lipschitz condition) and its proof are also given. Though this condition guarantees the convergence, it may not be met for an arbitrary deformation field. One should always check whether the inverse exists for the given forward deformation field by calculating its Jacobian. If nonpositive values of the Jacobian occur only for few voxels, this method will usually converge to a pseudoinverse. In case the iteration fails to converge, one should switch to other means of finding the inverse. We tested the proposed method on simulated 2D data and real 3D computed tomography data of a lung patient and compared our method with two implementations in the Insight Segmentation and Registration Toolkit (ITK). Typically less than ten iterations are needed for our method to get an inverse deformation field with clinically relevant accuracy. Based on the test results, our method is about ten times faster and yet ten times more accurate than ITK's iterative method for the same number of iterations. Simulations and real data tests demonstrated the efficacy and the accuracy of the proposed algorithm.


"I'll never drink like that again": characteristics of alcohol-related incidents and predictors of motivation to change in college students.
Alcohol use and its associated behaviors are among the most common reasons for medical treatment and disciplinary infractions among college students. The purpose of this study was to describe the characteristics of students who had recent serious alcohol-related incidents and to identify predictors of motivation to change alcohol use and heavy drinking in particular, with specific attention to gender. Students (N = 227; 52% female) who had been mandated to attend a session of alcohol education following alcohol-related medical treatment and/or a disciplinary infraction were assessed on their alcohol use, alcohol problems, characteristics of their alcohol-related incident, reactions to the incident, attributions about the incident, and motivation to change drinking and heavy drinking. Path and regression analyses were used to identify the individual and incident-related characteristics that were related to motivation to change. Perceived aversiveness of the incident was directly and positively related to motivation to change drinking and heavy drinking. Alcohol consumption in the month before the incident and past-year alcohol problems were negatively related to motivation to change heavy drinking, and women were more motivated to change heavy drinking than men. The more students consumed in the incident, the more likely they were to feel responsible for it, and the more responsible they felt about the incident, the greater its aversiveness. Individual and incident-related characteristics are both directly and indirectly associated with motivation to change following an alcohol-related incident, and therefore have implications for interventions with college drinkers who have experienced an alcohol-related incident.


Podocoryna loyola, n. sp. (Hydrozoa, Hydractiniidae): a probably introduced species on artificial substrate from southern Brazil.
Podocoryna loyola, a new hydractiniid species, has been found on artificial substrates in Baía de Paranaguá, southern coast of Brazil, since April 2007. Its main morphological characteristics are: (1) polymorphic colonies with reticular stolons or encrusting hydrorhiza not covered by periderm and smooth chitinous spines; (2) newly-released medusae with eight tentacles and small interradial gonads; (3) mature medusae with eight tentacles and unbranched oral lips; gastric peduncle absent. Molecular data show that P. loyola is distinct from all other examined species of Podocoryna, and from P. hayamaensis Hirohito (1988), its sister species from Japan. As the polyps having been noted only quite recently, and in having been found only on man-made objects in port areas and estuaries, the species is most likely exotic to the region.


Drugs associated with bullous pemphigoid. A case-control study.
Bullous pemphigoid is the most frequent autoimmune blistering disease. It occurs in the elderly. The cause of this disease is unknown, but cases of bullous pemphigoid have been occasionally attributed to drug therapy. We conducted a multicenter prospective case-control study looking at the drugs used on a long-term basis before the onset of the disease in 116 incident cases of bullous pemphigoid and 216 control patients with malignant or benign skin tumors. Case patients and control patients received many drugs on a long-term basis (mean +/-SD, 4.4+/-3.2 and 4.4+/-2.7 years respectively). Two classes of drugs, neuroleptics and diuretics, were used more frequently by case patients than control patients. Neuroleptics were used by 15.5% of case patients and 8.3% of control patients (adjusted odds ratios; 1.9; 95% confidence interval, 0.95 to 3.8). Diuretics were used by 36.2% of case patients and 24.5% of control patients (adjusted odds ratios, 1.8; 95% confidence interval, 1.1 to 2.9). Among neuroleptics, no specific drug emerged. The association with diuretics was only linked to aldosterone antagonists, which were taken by 12.9% of case patients and 4.6% of control patients (adjusted odds ratios, 3.1; 95% confidence interval, 1.4 to 7.1). These results suggest that some drug therapies may be a risk factor for bullous pemphigoid. The cause of this association should be further investigated.


A Software Tool for the Measurement of the Aortic Annulus Area by Means of Computed Tomography Image Analysis for the Planning of Transcatheter Aortic Valve Replacement (TAVR).
Cardiovascular diseases (CVD) are the leading cause of death globally, being the heart valve complications one of the five most common heart problems. The aim of this study is the development of a MATLAB-based software tool to obtain several measurements derived from the aortic annulus for the planning of transcatheter aortic valve replacement (TAVR). The proposed software tool utilizes computed tomography (CT) images to reconstruct a volume of the patient. This virtual volume is rotated to situate the images in the plane which cuts the most basal points of the three aortic valve cusps, namely the aortic annulus, and obtain the required measurements. Nevertheless, the computer-user interaction will be entirely based on 2-dimension techniques to reduce both the complexity of the app and the computational load. The program was validated in CT images of 10 subjects with diagnosed aortic stenosis. A comparison of the results with the measurements used in the real clinical practice showed no significant differences between both methods.Clinical Relevance- The resulting computer tool provides significant information about the diseased aortic valve. This will allow clinicians to select the right prosthetic heart valve. It represents a cheaper and less complex alternative to sophisticated software tools which are currently being used to plan the intervention.


Focus group study of public opinion about paying living kidney donors in Australia.
The unmet demand for kidney transplantation has generated intense controversy about introducing incentives for living kidney donors to increase donation rates. Such debates may affect public perception and acceptance of living kidney donation. This study aims to describe the range and depth of public opinion on financial reimbursement, compensation, and incentives for living kidney donors. Twelve focus groups were conducted with 113 participants recruited from the general public in three Australian states in February 2013. Thematic analysis was used to analyze the transcripts. Five themes were identified: creating ethical impasses (commodification of the body, quandary of kidney valuation, pushing moral boundaries), corrupting motivations (exposing the vulnerable, inevitable abuse, supplanting altruism), determining justifiable risk (compromising kidney quality, undue harm, accepting a confined risk, trusting protective mechanisms, right to autonomy), driving access (urgency of organ shortage, minimizing disadvantage, guaranteeing cost-efficiency, providing impetus, counteracting black markets), and honoring donor deservingness (fairness and reason, reassurance and rewards, merited recompense). Reimbursement and justifiable recompense are considered by the Australian public as a legitimate way of supporting donors and reducing disadvantage. Financial payment beyond reimbursement is regarded as morally reprehensible, with the potential for exploitative commercialism. Some contend that regulated compensation could be a defensible strategy to increased donation rates provided that mechanisms are in place to protect donors. The perceived threat to community values of human dignity, goodwill, and fairness suggests that there could be strong public resistance to any form of financial inducements for living kidney donors. Policy priorities addressing the removal of disincentives may be more acceptable to the public.


Modeling phosphate transport and removal in a compact bed filled with a mineral-based sorbent for domestic wastewater treatment.
Phosphorus filter units containing mineral-based sorbents with a high phosphate (PO4) binding capacity have been shown to be appropriate for removing PO4 in the treatment of domestic wastewater in on-site facilities. However, a better understanding of their PO4 removal mechanisms, and reactions that could lead to the formation of PO4 compounds, is required to evaluate the potential utility of candidate sorbents. Models based on data obtained from laboratory-scale experiments with columns of selected materials can be valuable for acquiring such understanding. Thus, in this study the transport and removal of PO4 in experiments with a laboratory-scale column filled with a commercial silicate-based sorbent were modeled, using the hydro-geochemical transport code PHREEQC. The resulting models, that incorporated the dissolution of calcite, kinetic constrains for the dissolution of calcium oxide (CaO) and wollastonite (CaSiO3), and the precipitation of amorphous tricalcium phosphate, Ca3(PO4)2, successfully simulated the removal of PO4 observed in the experiments.


[Criteria of the epidemiological surveillance of meningococcal infection].
The results of studies carried out with the use of the unified, specially developed methods in eight regions of the USSR are generalized. Basing on the analysis of the results, the leading role of serogroup A meningococci in the rise of morbidity is emphasized, the relation of the morbidity level to the serogroup composition of meningococci circulating among healthy population is revealed, the necessity of carrying out selective bacteriological surveys with a view to establish the serogroups of meningococci circulating among the population is shown. The expedient criteria to be used in the system of epidemiological surveillance of meningococcal infection are presented.


Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice.
Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4-/- and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4-/- mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.


O-Antigen Gene Clusters of Plesiomonas shigelloides Serogroups and Its Application in Development of a Molecular Serotyping Scheme.
Plesiomonas shigelloides is a Gram-negative, flagellated, rod-shaped, ubiquitous, and facultative anaerobic bacterium. It has been isolated from various sources, such as freshwater, surface water, and many wild and domestic animals. P. shigelloides is associated with diarrheal diseases of acute secretory gastroenteritis, an invasive shigellosis-like disease, and a cholera-like illness in humans. At present, 102 somatic antigens and 51 flagellar antigens of P. shigelloides have been recognized; however, very little is known about variations of O-antigens among P. shigelloides species. In this study, 12 O-antigen gene clusters of P. shigelloides, O2H1a1c (G5877), O10H41 (G5892), O12H35 (G5890), O23H1a1c (G5263), O25H3 (G5879), O26H1a1c (G5889), O32H37 (G5880), O33H38 (G5881), O34H34 (G5882), O66H3 (G5270), O75H34 (G5885), and O76H39 (G5886), were sequenced and analyzed. The genes that control O-antigen synthesis are present as chromosomal gene clusters that maps between rep and aqpZ, and most of the synthesis and translocation of OPS (O-specific polysaccharide) belongs to Wzx/Wzy pathway with the exception of O12, O25, and O66, which use the ATP-binding cassette (ABC) transporter pathway. Phylogenetic analysis of wzx and wzy show that the wzx and wzy genes are specific to individual O-antigens and can be used as targets in molecular typing. Based on the sequence data, an O-antigen specific suspension array that detects 12 distinct OPS' has been developed. This is the first report to catalog the genetic features of P. shigelloides O-antigen variations and develop a suspension array for the molecular typing. The method has several advantages over traditional bacteriophage and serum agglutination methods and lays the foundation for easier identification and detection of additional O-antigen in the future.


Electrical impedance spectroscopy as electrical biopsy for monitoring radiation sequelae of intestine in rats.
Electrical impedance is one of the most frequently used parameters for characterizing material properties. The resistive and capacitive characteristics of tissue may be revealed by electrical impedance spectroscopy (EIS) as electrical biopsy. This technique could be used to monitor the sequelae after irradiation. In this study, rat intestinal tissues after irradiation were assessed by EIS system based on commercially available integrated circuits. The EIS results were fitted to a resistor-capacitor circuit model to determine the electrical properties of the tissue. The variations in the electrical characteristics of the tissue were compared to radiation injury score (RIS) by morphological and histological findings. The electrical properties, based on receiver operation curve (ROC) analysis, strongly reflected the histological changes with excellent diagnosis performance. The results of this study suggest that electrical biopsy reflects histological changes after irradiation. This approach may significantly augment the evaluation of tissue after irradiation. It could provide rapid results for decision making in monitoring radiation sequelae prospectively.


Endoscopic management of benign recalcitrant esophageal strictures.
Benign esophageal strictures are one of the common clinical conditions managed by endoscopists. Nearly 90% of the benign esophageal strictures respond to endoscopic dilation. However, a small percentage of patients progress to recalcitrant strictures. The benign recalcitrant esophageal strictures are difficult to manage both medically and endoscopically as they do not respond to conventional treatment with proton pump inhibitors and esophageal dilations. Patients with benign recalcitrant esophageal strictures are at a high risk of developing debilitating malnutrition and morbidity due to severe dysphagia. This condition is associated with psychological trauma to patients as treatments are usually prolonged with poor outcomes. Also, this can be a financial burden on the healthcare industry due to several sessions of treatment. In this article, we discuss the classification of benign esophageal strictures, evidence-based treatment strategies, endoscopic procedural techniques, and complications of endoscopic interventions. We aim to guide providers in managing benign esophageal strictures with a focus on endoscopic management of benign recalcitrant esophageal strictures.


Characterization of lactococci isolated from milk produced in the Camembert region of Normandy.
Thirty-eight Lactococcus strains, isolated from raw milk produced in two dairy areas in Normandy, were identified at the phenotypic level. Only Lactococcus lactis strains with the lactis phenotype were found in the milk samples. Most strains fermented lactose (97%) and showed proteinase activity (76%). Isolates were characterized by RAPD technique and rRNA gene restriction analysis. More L. lactis strains with the lactis genotype were found in the first area, while L. lactis strains with the cremoris genotype predominated in the second area. RAPD was more efficient than rRNA gene restriction analysis in differentiating between strains with the subsp. lactis genotype. For L. lactis with the subsp. cremoris genotype, the second method gave a better result but there was poor discrimination between strains. Plasmid profiles were determined. Patterns ranged in size from 1.3 to 16.5 kbp, and 29 different profiles were found. Six groups of strains were determined, five of which were specific for the area of origin. It is suggested that the region of manufacture could influence organoleptic properties of cheeses because of different Lactococcus strains in the raw milk used for cheese making.


Automated Assessment of Prosody Production.
Assessment of prosody is important for diagnosis and remediation of speech and language disorders, for diagnosis of neurological conditions, and for foreign language instruction. Current assessment is largely auditory-perceptual, which has obvious drawbacks; however, automation of assessment faces numerous obstacles. We propose methods for automatically assessing production of lexical stress, focus, phrasing, pragmatic style, and vocal affect. Speech was analyzed from children in six tasks designed to elicit specific prosodic contrasts. The methods involve dynamic and global features, using spectral, fundamental frequency, and temporal information. The automatically computed scores were validated against mean scores from judges who, in all but one task, listened to "prosodic minimal pairs" of recordings, each pair containing two utterances from the same child with approximately the same phonemic material but differing on a specific prosodic dimension, such as stress. The judges identified the prosodic categories of the two utterances and rated the strength of their contrast. For almost all tasks, we found that the automated scores correlated with the mean scores approximately as well as the judges' individual scores. Real-time scores assigned during examination - as is fairly typical in speech assessment - correlated substantially less than the automated scores with the mean scores.


An Environmental Friendly Fluorinated Oligoamide for Producing Nonwetting Coatings with High Performance on Porous Surfaces.
The changes in the surface wettability of many materials are receiving increased attention in recent years. It is not too hard to fabricate resistant hydrophobic surfaces through products bearing both hydrophobic and reactive hydrophilic end groups. More challenging is obtaining resistant nonwetting surfaces through noncovalent reversible bonds. In this work, a fluorinated oligo(ethylenesuccinamide), soluble in solvent benign for operators and environment, has been synthesized. It contains two opposite functional groups (perfluoropolyether segments and amidic groups) (SC2-PFPE) that provide water repellency while hydrophilicity is retained. Its performance has been tested on porous calcarenite and investigated by magnetic resonance imaging, water capillary absorption, and vapor diffusivity tests. The results demonstrate that SC2-PFPE modifies the wettability of porous substrates in a drastic and durable way and reduces the vapor condensation inside the pore space due to the perfluoropolyether segments that act at the air/surface interface.


Identification of a Novel Pseudo-Natural Product Type IV IDO1 Inhibitor Chemotype.
Natural product (NP)-inspired design principles provide invaluable guidance for bioactive compound discovery. Pseudo-natural products (PNPs) are de novo combinations of NP fragments to target biologically relevant chemical space not covered by NPs. We describe the design and synthesis of apoxidoles, a novel pseudo-NP class, whereby indole- and tetrahydropyridine fragments are linked in monopodal connectivity not found in nature. Apoxidoles are efficiently accessible by an enantioselective [4+2] annulation reaction. Biological evaluation revealed that apoxidoles define a new potent type IV inhibitor chemotype of indoleamine 2,3-dioxygenase 1 (IDO1), a heme-containing enzyme considered a target for the treatment of neurodegeneration, autoimmunity and cancer. Apoxidoles target apo-IDO1, prevent heme binding and induce unique amino acid positioning as revealed by crystal structure analysis. Novel type IV apo-IDO1 inhibitors are in high demand, and apoxidoles may provide new opportunities for chemical biology and medicinal chemistry research.


Sulfated small molecules targeting eBV in Burkitt lymphoma: from in silico screening to the evidence of in vitro effect on viral episomal DNA.
Epstein-Barr virus (EBV) infects more than 90% of the world population. Following primary infection, Epstein-Barr virus persists in an asymptomatic latent state. Occasionally, it may switch to lytic infection. Latent EBV infection has been associated with several diseases, such as Burkitt lymphoma (BL). To date, there are no available drugs to target latent EBV, and the existing broad-spectrum antiviral drugs are mainly active against lytic viral infection. Thus, using computational molecular docking, a virtual screen of a library of small molecules, including xanthones and flavonoids (described with potential for antiviral activity against EBV), was carried out targeting EBV proteins. The more interesting molecules were selected for further computational analysis, and subsequently, the compounds were tested in the Raji (BL) cell line, to evaluate their activity against latent EBV. This work identified three novel sulfated small molecules capable of decreasing EBV levels in a BL. Therefore, the in silico screening presents a good approach for the development of new anti-EBV agents.


Towards the resolution of a long-standing evolutionary question: muscle identity and attachments are mainly related to topological position and not to primordium or homeotic identity of digits.
Signaling for limb bone development usually precedes that for muscle development, such that cartilage is generally present before muscle formation. It remains obscure, however, if: (i) tetrapods share a general, predictable spatial correlation between bones and muscles; and, if that is the case, if (ii) such a correlation would reflect an obligatory association between the signaling involved in skeletal and muscle morphogenesis. We address these issues here by using the results of a multidisciplinary analysis of the appendicular muscles of all major tetrapod groups integrating dissections, muscle antibody stainings, regenerative and ontogenetic analyses of fluorescently-labeled (GFP) animals, and studies of non-pentadactyl human limbs related to birth defects. Our synthesis suggests that there is a consistent, surprising anatomical pattern in both normal and abnormal phenotypes, in which the identity and attachments of distal limb muscles are mainly related to the topological position, and not to the developmental primordium (anlage) or even the homeotic identity, of the digits to which they are attached. This synthesis is therefore a starting point towards the resolution of a centuries-old question raised by authors such as Owen about the specific associations between limb bones and muscles. This question has crucial implications for evolutionary and developmental biology, and for human medicine because non-pentadactyly is the most common birth defect in human limbs. In particular, this synthesis paves the way for future developmental experimental and mechanistic studies, which are needed to clarify the processes that may be involved in the elaboration of the anatomical patterns described here, and to specifically test the hypothesis that distal limb muscle identity/attachment is mainly related to digit topology.


Breastfeeding-associated hypernatremia: are we missing the diagnosis?
To assess the incidence and complications of breastfeeding-associated hypernatremic dehydration among hospitalized neonates. A retrospective study was conducted at Children's Hospital of Pittsburgh over a 5-year period, to identify otherwise healthy term and near-term (> or =35 weeks of gestation) breastfed neonates (<29 days of age) who were admitted with serum sodium concentrations of > or =150 mEq/L and no explanation for hypernatremia other than inadequate milk intake. The incidence of breastfeeding-associated hypernatremic dehydration among 3718 consecutive term and near-term hospitalized neonates was 1.9%, occurring for 70 infants. These infants were born primarily to primiparous women (87%) who were discharged within 48 hours after birth (90%). The most common presenting symptom was jaundice (81%). Sixty-three percent of infants underwent sepsis evaluations with lumbar puncture. No infants had bacteremia or meningitis. Infants had hypernatremia of moderate severity (median: 153 mEq/L; range: 150-177 mEq/L), with a mean weight loss of 13.7%. Nonmetabolic complications occurred for 17% of infants, with the most common being apnea and/or bradycardia. There were no deaths. Hypernatremic dehydration requiring hospitalization is common among breastfed neonates. Increased efforts are required to establish successful breastfeeding.


Electrical Tuning of the SERS Enhancement by Precise Defect Density Control.
Surface-enhanced Raman scattering (SERS) has been widely established as a powerful analytical technique in molecular fingerprint recognition. Although conventional noble metal-based SERS substrates show admirable enhancement of the Raman signals, challenges on reproducibility, biocompatibility, and costs limit their implementations as the preferred analysis platforms. Recently, researches on SERS substrates have found that some innovatively prepared metal oxides/chalcogenides could produce noble metal comparable SERS enhancement, which profoundly expanded the material selection. Nevertheless, to tune the SERS enhancement of these materials, careful experimental designs and sophisticated processes were needed. Here, an electrically tunable SERS substrate based on tungsten oxides (WO3-x) is demonstrated. An electric field is used to introduce the defects in the oxide on an individual substrate, readily invoking the SERS detection capability, and further tuning the enhancement factor is achieved through electrical programming of the oxide leakage level. Additionally, by virtue of in situ tuning the defect density and enhancement factor, the substrate can adapt to different molecular concentrations, potentially improving the detection range. These results not only help build a better understanding of the chemical mechanism but also open an avenue for engaging non-noble metal materials as multifunctional SERS substrates.


An intracellular study of rubrospinal and rubro-bulbospinal control of lumbar gamma-motoneurones.
The actions elicited by electrical stimulation of the rubrospinal path in NR (nucleus ruber), and by stimulation of the rubro-bulbospinal path in MesADC (mesencephalic area for dynamic control), were studied with intra-, juxta- or extracellular recordings in lumbar gamma-motoneurones of cats anaesthetized with chloralose. The results were obtained during a series of experiments in which reflex effects from muscle, skin and joint afferents were also investigated. 90 cells tested with stimulation both in NR and in MesADC were classified (cf. Appelberg 1981) as dynamic (influenced from MesADC) or static (not influenced). 84 of these gamma-cells responded to stimulation in the red nucleus. The same response pattern was found for dynamic and static gamma-cells. For flexor cells, excitation was by far predominant while equal numbers of extensor cells showed excitatory and inhibitory effects. The shortest route to both static and dynamic gamma-cells was disynaptic. With stimulation of the rubro-bulbospinal path, excitatory effects were more than twice as frequent as inhibitory effects. No clearcut difference was seen between extensor and flexor cells. The segmental latency for rubro-bulbospinally mediated excitatory effects could be measured for only one cell, and it is tentatively suggested that the pathway to this dynamic gamma-motoneurone involves one or two interneurones more than in the rubrospinal pathway. Spontaneous activity was significantly more common among the dynamic cells, but the axonal conduction velocities of dynamic and static cells did not differ. The similarities between rubro-spinal effects on alpha-motoneurones and both classes of gamma-motoneurones indicate that the rubrospinal tract has the ability to coactivate alpha- and gamma-motoneurones (Granit 1955, 1979). The comparison of the properties of the population of gamma-cells classified as dynamic or static showed marked differences strengthening the reliability of the previously introduced classification method.


Influence of particulate alkaline biomaterial remnants in dentin on the adhesion of two resin-based bonding systems.
To study aimed to evaluate the influence of infiltrated alkaline biomaterials on the bond strength of composite obtained with etch and rinse and universal adhesive systems. Coronal dentin of extracted human molars was exposed and infiltrated with calcium hydroxide, MTA, or bioactive glass 45S5 powder. Non-infiltrated dentin specimens served as controls. Subsequently, dentin was either acid-etched or not, and remaining alkali content was measured by pH induction in water. Shear bond strength of an etch-and rinse system (Adper Single Bond 2) on etched dentin was then compared to that of a universal counterpart (Single Bond [(Scotchbond) Universal] by the same manufacturer. Data was compared between groups using one-way ANOVA and Tukey's HSD. On sound dentin, the etch-and-rinse system adhered stronger than the universal system (p < .05). All particles rendered the dentin alkaline. Acid etching reduced the alkali content in the infiltrated dentin. However, bond strength values were stronger with the universal system without etching than with the etch-and rinse counterpart, which lost more than 60% of its adhesiveness. The universal adhesive system was less susceptible to alkaline contamination of the dentin than the etch-and-rinse counterpart. Based on the similar composition of the two systems under investigation, this is likely to the due to its 10-MDP component.


Overview of Antagonists Used for Determining the Mechanisms of Action Employed by Potential Vasodilators with Their Suggested Signaling Pathways.
This paper is a review on the types of antagonists and the signaling mechanism pathways that have been used to determine the mechanisms of action employed for vasodilation by test compounds. Thus, we exhaustively reviewed and analyzed reports related to this topic published in PubMed between the years of 2010 till 2015. The aim of this paperis to suggest the most appropriate type of antagonists that correspond to receptors that would be involved during the mechanistic studies, as well as the latest signaling pathways trends that are being studied in order to determine the route(s) that atest compound employs for inducing vasodilation. The methods to perform the mechanism studies were included. Fundamentally, the affinity, specificity and selectivity of the antagonists to their receptors or enzymes were clearly elaborated as well as the solubility and reversibility. All the signaling pathways on the mechanisms of action involved in the vascular tone regulation have been well described in previous review articles. However, the most appropriate antagonists that should be utilized have never been suggested and elaborated before, hence the reason for this review.


Immunoadsorption in nephrotic syndrome: Where are we now and where are we going from here?
Idiopathic nephrotic syndrome (INS) is characterized by three different entities, namely minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN). While there is an increasing understanding of primary MN with the discovery of antibodies directed against phospholipase A2 receptor (PLA2R Ab) and thrombospondin type 1 domain-containing 7A, circulatory factors causative of inducing MCD and FSGS remain in part elusive. Extracorporeal treatment forms (mostly plasma exchange) have been reserved for patients with either a disease course refractory to commonly prescribed immunosuppressive drugs or to patients with recurrence after kidney transplantation. There is a paucity of data supporting the use of immunoadsorption (IAS) in the management of MCD and MN and evidence to perform LDL-apheresis in the former is limited to reports from Japan. Treatment with IAS in primary FSGS has shown mixed responses, possibly biased by including treatment-resistant cases in the absence of genetic testing. In those with recurrence of the disease following kidney transplantation, IAS has shown high remission rates with an acceptable safety profile. There is a need to compare IAS to plasma exchange (PLEX) in this indication and due to a higher amount of plasma processed during one session, IAS may have advantages over PLEX. Removal of PLA2R Ab by IAS is currently being tested in a phase II clinical trial. More clinical trials in a prospective and randomized fashion need to be designed to prove the concept that IAS may be a treatment option for INS. While PLEX is still the leading extracorporeal treatment form in these indications, this review aims to highlight the efficacy and safety of IAS in the management of INS.


New quantitative approaches reveal the spatial preference of nuclear compartments in mammalian fibroblasts.
The nuclei of higher eukaryotic cells display compartmentalization and certain nuclear compartments have been shown to follow a degree of spatial organization. To date, the study of nuclear organization has often involved simple quantitative procedures that struggle with both the irregularity of the nuclear boundary and the problem of handling replicate images. Such studies typically focus on inter-object distance, rather than spatial location within the nucleus. The concern of this paper is the spatial preference of nuclear compartments, for which we have developed statistical tools to quantitatively study and explore nuclear organization. These tools combine replicate images to generate 'aggregate maps' which represent the spatial preferences of nuclear compartments. We present two examples of different compartments in mammalian fibroblasts (WI-38 and MRC-5) that demonstrate new knowledge of spatial preference within the cell nucleus. Specifically, the spatial preference of RNA polymerase II is preserved across normal and immortalized cells, whereas PML nuclear bodies exhibit a change in spatial preference from avoiding the centre in normal cells to exhibiting a preference for the centre in immortalized cells. In addition, we show that SC35 splicing speckles are excluded from the nuclear boundary and localize throughout the nucleoplasm and in the interchromatin space in non-transformed WI-38 cells. This new methodology is thus able to reveal the effect of large-scale perturbation on spatial architecture and preferences that would not be obvious from single cell imaging.


[The characteristics of the clinical picture and outcome of viral hepatitis B].
Results are reported of a study of the clinical course and outcomes of viral hepatitis B. The etiology was confirmed in all patients by detection of the superficial antigen of hepatitis B virus in the blood serum. A clinico-physiological and biochemical follow-up revealed that complete clinical recovery is slow, though the condition of most convalescents does not suffer practically. Viral hepatitis B convalescents revealed in the long-term follow-up residual clinico-biochemical changes.


Individualization of immunosuppressive therapy. III. Sirolimus associated with a reduced incidence of malignancy.
We examined the occurrence of neoplasms among 1008 renal transplant recipients treated with a sirolimus-cyclosporine (CsA) +/- prednisone (Pred) regimen. A comprehensive database of demographic, laboratory, clinical, and histopathologic features of these patients all followed in our transplant center was analyzed using Student t test and Mann-Whitney U test for continuous and chi-square test for categorical variables. Comparisons were performed with information in the Israel Penn International Transplant Tumor Registry (IPITTR). During the mean patient follow-up of 62.3 +/- 26.1 months (range 27.1 to 131), 36 tumors occurred in 35 patients (3.6%) at 32.5 +/- 29.8 months. The most common neoplasms were skin tumors (2.4%), a value that was significantly lower than the 6% rate observed with CsA-azathioprine-Pred treatment. Also, the 0.4% incidence of posttransplant lymphoproliferative disorders and 0.2% incidence of renal cell carcinomas were less than half of those previously reported with a combination of tacrolimus and mycophenolate mofetil. The distribution of tumor types was similar to that reported to the IPITTR. The mean trough drug concentrations in affected recipients at the time of diagnosis were within the putative target ranges. Renal transplant recipients treated with the sirolimus-CsA +/- Pred combination showed a low incidence of tumors of similar types as those encountered with other regimens.


Do thrombophilias cause placenta-mediated pregnancy complications?
There has been an sudden increase of knowledge about thrombophilias in the last decade as new thrombophilias are discovered and new associations are explored. It is now evident that thrombophilias are common and that the clinical consequences of having a thrombophilia do not appear to be limited to venous thromboembolism. The placenta-mediated pregnancy complications are also common (more than one in six pregnancies are affected) and include pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. These complications as a whole are the leading causes of maternal and neonatal morbidity in the developed world. Evidence has emerged to suggest that thrombophilic women may be at higher risk of developing these placenta-mediated pregnancy complications. However, is this evidence mature enough to claim that a causal association is proven? Is the evidence strong enough to recommend anticoagulant prophylaxis? We suggest that causality is not yet proven and that the data to support management with anticoagulant prophylaxis in thrombophilic pregnancies is too immature to consider this an established intervention.


Firearm Deaths are Increasing and Endemic in the USA: It is a Problem of Suicides and Not Homicides.
To analyze and report on the changes in epidemiology traumatic causes of death in the USA. Data were extracted from the annual National Vital Statistics Reports (2008-2017) from Center for Disease Control and analyzed for trends during the time period given. Generalized additive model was applied to evaluate the significance of trend using R software. Firearm deaths (39,790) and firearm death rate (12.2/100,000) in 2017 were the highest reported, and this increasing trend was significant (p < 0.001) the last ten years. Deaths from motor vehicle crash (MVC) and firearm homicides did not change significantly during the same time period. Firearm deaths were lower than MVC deaths by 21% (8,197/39,790) in 2008, but after 10 years, the difference was only 1% (458/40,231). Years of life lost from firearms is now higher than MVC. Suicides by firearm in 2017 were the highest reported at 23,854/39,773 (60%). In 2017, suicides by firearm victims were predominantly white 20,328/23,562 (85%), men 20,362/23,562 (86%), and the largest group was between the ages of 55-64. Death from firearms in the USA is increasing and endemic. They were the highest ever reported in 2017 by the CDC. While deaths from MVC used to be the main cause of traumatic death in the USA, deaths from firearms now almost equal it. Calculated years of life lost from firearms is now more than from MVC. Most firearm deaths are not from homicides but are from suicides, and they are predominantly in white older males of the baby boomer generation (born 1946-1964).


Promoter Boundaries for the luxCDABE and betIBA-proXWV Operons in Vibrio harveyi Defined by the Method Rapid Arbitrary PCR Insertion Libraries (RAIL).
Experimental studies of transcriptional regulation in bacteria require the ability to precisely measure changes in gene expression, often accomplished through the use of reporter genes. However, the boundaries of promoter sequences required for transcription are often unknown, thus complicating the construction of reporters and genetic analysis of transcriptional regulation. Here, we analyze reporter libraries to define the promoter boundaries of the luxCDABE bioluminescence operon and the betIBA-proXWV osmotic stress operon in Vibrio harveyi We describe a new method called rapid arbitrary PCR insertion libraries (RAIL) that combines the power of arbitrary PCR and isothermal DNA assembly to rapidly clone promoter fragments of various lengths upstream of reporter genes to generate large libraries. To demonstrate the versatility and efficiency of RAIL, we analyzed the promoters driving expression of the luxCDABE and betIBA-proXWV operons and created libraries of DNA fragments from these loci fused to fluorescent reporters. Using flow cytometry sorting and deep sequencing, we identified the DNA regions necessary and sufficient for maximum gene expression for each promoter. These analyses uncovered previously unknown regulatory sequences and validated known transcription factor binding sites. We applied this high-throughput method to gfp, mCherry, and lacZ reporters and multiple promoters in V. harveyi We anticipate that the RAIL method will be easily applicable to other model systems for genetic, molecular, and cell biological applications.IMPORTANCE Gene reporter constructs have long been essential tools for studying gene regulation in bacteria, particularly following the recent advent of fluorescent gene reporters. We developed a new method that enables efficient construction of promoter fusions to reporter genes to study gene regulation. We demonstrate the versatility of this technique in the model bacterium Vibrio harveyi by constructing promoter libraries for three bacterial promoters using three reporter genes. These libraries can be used to determine the DNA sequences required for gene expression, revealing regulatory elements in promoters. This method is applicable to various model systems and reporter genes for assaying gene expression.


Hybrid nanoparticle composites applied to photodynamic therapy: strategies and applications.
Photodynamic therapy (PDT), as a robust strategy, has long been applied to cancer treatment owing to the meaningful breakthroughs and unique advantages, including ignorable invasiveness and spatio-temporal selectivity. Numerous PDT agents, especially hybrid nanoparticle composite (hybrid)-based sensitizers consisting of an organic polymer and inorganic nanoparticles (NPs), feature the synergetic pros of the components, which have unlocked the additional potentials of PDT. Although reviews relating to the applications of hybrids to PDT have been previously reported, most of them only focus on the designs of smart hybrids integrating multimodal imaging-guided multiple treatment modalities. Traditional PDT treatment has several limitations, such as inadequate PDT agents accumulating in cancer tissues, inferior PDT effect due to the devastating cancer hypoxia environment, relevant systemic toxicity in non-intelligent stimulation response treatment systems, and serious dependence of PDT on external light sources. Many strategies have been developed for overcoming these limitations, including improvement of cancer-homing ability by introducing active targeting groups, remodeling of the cancer hypoxia environment through oxygen regulators, intratumor release of ROS through activatable molecules, and replacement of laser light by X-rays or self-luminescence. This review aims to summarize the most recent advances in designing hybrids for improving the therapeutic efficacy of PDT.


Molecular abnormalities of mdm-2 in human sarcomas.
MDM-2 is an oncoprotein that seems to function, at least in part, by interacting with the p53 protein and modulating its tumor-suppressing activity. The MDM-2 gene codes for p57, p74, p76, p85, and p90 proteins. Overexpression of only the p90 MDM-2 protein has been reported in sarcomas showing MDM-2 gene amplification. In addition, post-transcriptional mechanisms have been demonstrated to play a role in the expression of MDM-2 proteins. We investigated MDM-2 gene amplification, mRNA and protein levels in various cases of sarcomas. We found MDM-2 gene amplification in 12 (26%) of 46 cases of sarcoma: 11 of 13 cases of liposarcoma and 1 of 6 cases of malignant fibrous histiocytoma. The MDM-2 amplification correlated with the presence of elevated levels of mRNA and protein in the liposarcomas. In sarcomas other than liposarcomas, mRNA was overexpressed in 7 (30%) of 23 cases, without MDM-2 amplification. In 15 (62.5%) of 24 cases of sarcoma and in 1 case of lipoma the MDM-2 protein was overexpressed as shown by Western blot analysis. Interestingly, p57 not p90 was the most commonly overexpressed MDM-2 protein. These data indicate that the molecular abnormalities affecting MDM-2 expression in cases of sarcoma include transcriptional, post-transcriptional, and gene dosage (amplification) mechanisms. Furthermore, our findings suggest that MDM-2 p57 protein may be as important as p90 in the pathogenesis of human sarcomas.


Psychosis as a presentation of physical disease in adolescence: a case of Niemann-Pick disease, type C.
This study reports the case of a 16-year-old male who presented with a history of prominent psychotic symptoms and paranoid delusions which overshadowed subtle signs and symptoms of cognitive and motor dysfunction. Intensive neurobehavioral and biochemical investigations eventually led to the diagnosis of Niemann-Pick disease, type C (NPC), an autosomal recessively inherited storage disease that is associated with the accumulation of cholesterol in lysosomes and difficulties in the processing of exogenously derived cholesterol. Clues to the presence of a neurological disorder included: a history of insidiously declining academic and athletic performance which antedated the onset of psychosis; abnormalities on mental status examination, including psychomotor slowing, memory difficulties, and impairment of higher attentional functions; physical findings of subtle downgaze impairment, mild symmetrical hyperreflexia, and lower-extremity hypertonia with flexor plantar responses, marked impairment of upper-extremity rapid alternating movements, action tremor, and bilateral posturing with stress gait maneuvers. This case demonstrates the importance of careful and persistent neurodiagnostic evaluation in adolescents with psychotic presentations, particularly when cognitive and motor deterioration is suspected, and even when head CT and MRI scans are judged to be normal.


Raised enzyme markers of chronic inflammation in asymptomatic farmers' lung.
Subclinical inflammatory activity may be one of the factors which influences the variable natural history of farmers' lung. Serum lysozyme (LYS) and angiotensin converting enzyme (ACE) have been measured in 52 farmers with a previous history of farmers' lung and in 51 healthy control farmers. The group with farmers' lung assessed during the winter, although having had no recent acute symptoms, had significantly higher levels of LYS and ACE compared to both healthy control farmers seen in winter and farmers' lung subjects seen in summer. There was a mild but significant negative correlation between LYS and farm size in the farmers' lung subjects assessed in winter. The results suggest that active inflammation may be present in subjects with farmers' lung in the absence of acute symptoms during the season when dust exposure occurs as the result of feeding cattle.


Brief report: longitudinal improvements in the quality of joint attention in preschool children with autism.
Children with autism exhibit deficits in their quantity and quality of joint attention. Early autism intervention studies rarely document improvement in joint attention quality. The purpose of this study was to determine whether there was a change in joint attention quality for preschoolers with autism who were randomized to a joint attention intervention, symbolic play intervention, or a control group. Quality was defined as shared positive affect during joint attention as well as shared positive affect and utterances during joint attention. Interactions of group and time were found for both types of joint attention quality. During the follow up visits, the joint attention and symbolic play intervention groups produced more of these two types of joint attention quality than the control group.


Occurrence of butyrylcholinesterase polymorphisms in patients undergoing surgery in Slovakia.
Post-operative residual curarization is a persisting problem, characterized by muscle fatigue, exhaustion or paresis, caused by the use of neuromuscular blocking agents with prolonged postoperative effect. Genetically, determined changes in cholinesterase activity can be a major reason for persistent muscle blockade after administration of muscle relaxants. Regarding the subsistence of polymorphisms in the plasma cholinesterase gene causing change in enzyme activity and metabolism of applied drugs, we investigated the frequency of two polymorphisms known to reduce its activity significantly in patients undergoing surgery. Primary results show a relatively high occurrence of plasma cholinesterase K risk allele (18.75%). Characterization of the lacking information about genetic background of changes in plasma cholinesterase activity within Slovakia may allow for easier decision-making in clinical practice when selecting alternative neuromuscular blocking and also reversal agents.


Environmentally benign dry-gel conversions of Zr-based UiO metal-organic frameworks with high yield and the possibility of solvent re-use.
Herein we report an alternative synthesis method for Zr-based UiO metal-organic frameworks (MOFs), namely dry-gel conversion (DGC). It was possible to synthesize nano- to microsized UiO-66, UiO-66-NH2 and UiO-67 with high crystallinity, high surface area and increased yield using only one-sixth or less of the solvent volume compared to the solution synthesis on the same scale. Additionally, it is shown that solvent re-use is possible over at least five synthesis runs making the DGC method an ecological and extremely solvent-economical route to obtain Zr-based UiO-MOFs with reproducible results.


Glow Discharge Plasma Ionization Mass Spectrometry for Direct Detection of Oxygenated Organic Compounds in the Gas-phase.
This study describes a direct analysis of oxygenated organic compounds, such as ketones, esters and ethers, rapidly and easily using a soft plasma ionization (SPI) source combined with a Q-mass spectrometer. A related molecular ion, [2M+H]+, in which a sample molecule (M) can undergo protonation via water clusters, such as [(H2O)n+H]+ and [N2(H2O)n+H]+, in an ambient air glow discharge plasma, can be dominantly detected as a base peak with little or no fragmentation at a pressure of several kPa. Oxygenated organic compounds with high proton affinity were found to generate their dimers through the hydrogen bonding interaction at higher pressures. A deuterated solvent was used to examine whether or not the adduct ion of analyte was derived from the solvent. The formation of [2M+H]+ strongly depended on the time. A two-dimensional spectrometer was used to obtain the distribution of several excited species and then to confirm the ionization reactions of the analyte in the SPI source. The sample molecule would be readily ionized through Penning-type collisions with excited N2, which causes fragmentation for oxygenated compounds due to the lower pressures (approx. 1.0 kPa) while it is ionized by an attachment with protons from water clusters at higher pressures (several kPa). The SPI source can be a new and powerful tool for soft ionization in direct analysis of volatile organic compounds (VOCs).


Initial Gamma Knife radiosurgery for nonfunctioning pituitary adenomas.
Nonfunctioning pituitary adenomas (NFAs) are the most common type of pituitary adenoma and, when symptomatic, typically require surgical removal as an initial means of management. Gamma Knife radiosurgery (GKRS) is an alternative therapeutic strategy for patients whose comorbidities substantially increase the risks of resection. In this report, the authors evaluated the efficacy and safety of initial GKRS for NFAs. An international group of three academic Gamma Knife centers retrospectively reviewed outcome data in 569 patients with NFAs. Forty-one patients (7.2%) underwent GKRS as primary management for their NFAs because of an advanced age, multiple comorbidities, or patient preference. The median age at the time of radiosurgery was 69 years. Thirty-seven percent of the patients had hypopituitarism before GKRS. Patients received a median tumor margin dose of 12 Gy (range 6.2-25.0 Gy) at a median isodose of 50%. The overall tumor control rate was 92.7%, and the actuarial tumor control rate was 94% and 85% at 5 and 10 years postradiosurgery, respectively. Three patients with tumor growth or symptom progression underwent resection at 3, 3, and 96 months after GKRS, respectively. New or worsened hypopituitarism developed in 10 patients (24%) at a median interval of 37 months after GKRS. One patient suffered new-onset cranial nerve palsy. No other radiosurgical complications were noted. Delayed hypopituitarism was observed more often in patients who had received a tumor margin dose > 18 Gy (p = 0.038) and a maximum dose > 36 Gy (p = 0.025). In this study, GKRS resulted in long-term control of NFAs in 85% of patients at 10 years. This experience suggests that GKRS provides long-term tumor control with an acceptable risk profile. This approach may be especially valuable in older patients, those with multiple comorbidities, and those who have endocrine-inactive tumors without visual compromise due to mass effect of the adenoma.


Quantification of superoxide and hydrogen peroxide in leaves.
Reactive oxygen species (ROS) are produced in plants under both non-stressful and stressful conditions. Various histochemical staining methods have been developed and are widely used to visualize ROS accumulation sites. In contrast to qualitative analysis, quantification of ROS has been time- and labor consuming. As a consequence, the number of samples, which could be analyzed in parallel, has been limited. To overcome this problem, we introduce an improved semiquantitative method, in which ROS levels are quantified after histochemical staining in plant organs with the digital image analysis package ImageJ.


The decline in China's fertility level: a decomposition analysis.
Many factors have contributed to the decline in China's fertility level. Using China's population census data from 1990, 2000 and 2010, the present study investigates the factors causing the decline in China's fertility rate by decomposing changes in two fertility indices: the total fertility rate (TFR) and the net reproduction rate (NRR). The change in the TFR is decomposed into the change in the marital fertility rate (MFR) and the change in the proportion of married women (PMW). Four factors contribute to the change in the NRR. The following are the main findings. A drop in the MFR caused a decrease in the TFR and the NRR between 1989 and 2000. However, the change in MFR increased TFR and NRR between 2000 and 2010. Marriage postponement caused a decline in the fertility level between 1989 and 2000 as well as between 2000 and 2010. The effect of the MFR and marriage postponement varied with age and region and also between urban and rural areas.


Interleukin 18: a biomarker for differential diagnosis between adult-onset Still's disease and sepsis.
The differential diagnosis between rheumatic diseases and infectious conditions is a great challenge in clinical practice. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory syndrome that shares several clinical and laboratory variables with sepsis. Interleukin (IL)-18 is overexpressed in AOSD, suggesting a possible role as a disease biomarker. The aim of our study was to detect IL-18 serum levels in a cohort of patients with AOSD and sepsis and to address its possible role as a biomarker for differential diagnosis. A group of unselected patients with AOSD diagnosed according to the Yamaguchi criteria and consecutive patients with sepsis diagnosed according to the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference criteria were enrolled. The clinical and laboratory data were collected. In the AOSD group, disease activity was assessed by Pouchot's and Rau's criteria. IL-18 serum levels were detected by ELISA. Thirty-nine patients with AOSD and 18 patients with sepsis were enrolled. Two out of 18 patients with sepsis (11.1%) also fulfilled the Yamaguchi criteria. A significant difference was found in IL-18 serum levels between patients with active and inactive disease (p < 0.001), and it positively correlated with disease activity (p = 0.0003), ferritin serum level (p = 0.016), and erythrocyte sedimentation rate (p = 0.041). IL-18 was significantly increased in patients with AOSD when compared with sepsis (p = 0.014). For a cutoff of 148.9 pg/ml, this test had a specificity of 78.3% and a sensitivity of 88.6%. We have demonstrated that IL-18 can be a biomarker for differential diagnosis between AOSD and sepsis.


Modification of Dietary Fibers to Valorize the By-Products of Cereal, Fruit and Vegetable Industry-A Review on Treatment Methods.
Many by-products originating from cereal, fruit and vegetable industries contain quite high amounts of dietary fiber (DF), which play an important role in maintaining the healthy state of the human body. Nevertheless, huge proportions of these by-products are still underutilized as feed ingredients, to generate energy within an anaerobic digestion plant or even landfilled. One of the biggest hindrances in the valorization of such by-products is their very low soluble dietary fiber (SDF) to insoluble dietary fiber (IDF) ratios, impairing their nutritional functionality, palatability and technological applicability. Therefore, it is of interest to develop methods that can enhance the SDF to IDF ratio and that can be applied to the by-product streams of the food industry, enabling better valorization perspectives for human nutrition purposes. In this regard, the review paper provides an overview of existing technologies to modify the SDF to IDF ratio in by-products of the food industry by means of physical, chemical and biological treatments. For each type of treatment, available data on application examples including achieved increases in SDF contents are given. Additionally, a comparative discussion regarding the advantages and disadvantages of these methods is provided.


Ruptured cerebral aneurysm in the early stage of life--a congenital origin?
We report the case of a large fusiform aneurysm of the anterior cerebral artery in a 3-month-old girl presenting with generalized seizures and complicated by a cardiorespiratory arrest needing resuscitation. The native cerebral CT scan revealed a diffuse subarachnoid hemorrhage (Fischer III grade); CT angiography showed an aneurysm of the distal A1 segment of the anterior cerebral artery (ACA). Successful treatment was achieved through surgical trapping of the aneurysm and sacrifice of the distal A1 segment. A histological study of the aneurysmal wall revealed the absence of elastic fibers in an otherwise fibromuscular media and showed no signs of previous hemorrhage. Intracranial aneurysms of the ACA are very rare in the early stage of life and their pathogenesis is not clear. This case is of interest as the location and shape of the aneurysm, the absence of relevant familial and medical history, and the histopathological findings raise the hypothesis of a congenital origin. It further describes the value of CT angiography for studying aneurysms in the very young.


[HIV infection in pregnant women--clinical findings and treatment].
The paper reviews HIV infection in pregnancy. We have mainly used PubMed for literature searches with focus on risk factors for vertical infection and measures to prevent mother-to-child transmission. The risk of vertical HIV-transmission is greatest when the mother has high levels of viraemia. Antiviral treatment decreases the fetal risk. When the viral load is low, i.e. HIV-RNA below 1000 copies/ml, the risk of infection of the fetus is small; individually adapted antiviral treatment is indicated to obtain this goal. Increased risk of infection of the fetus may occur as a result of vaginal bleeding, amniocentesis, vaginal delivery, the use of scalp electrodes and fetal scalp pH measurement. The use of vacuum extraction and forceps delivery should be avoided if possible. An important factor associated with increased fetal risk is long lasting rupture of the membranes (> 4 hours). Elective delivery by Caesarean section at 38th week, before labour and rupture of the membranes, is advocated. A Caesarean section may, however, cause complications, and vaginal delivery at term may be considered when the viraemia is low (HIV-RNA < 1000 copies/ml). Amniotomy and long-standing rupture of the membranes should be avoided, as should breastfeeding.