A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases.
The different members of the vascular endothelial growth factor (VEGF) family act as key regulators of endothelial cell function controlling vasculogenesis, angiogenesis, vascular permeability and endothelial cell survival. In this study, we have functionally characterized a novel member of the VEGF family, designated VEGF-E. VEGF-E sequences are encoded by the parapoxvirus Orf virus (OV). They carry the characteristic cysteine knot motif present in all mammalian VEGFs, while forming a microheterogenic group distinct from previously described members of this family. VEGF-E was expressed as the native protein in mammalian cells or as a recombinant protein in Escherichia coli and was shown to act as a heat-stable, secreted dimer. VEGF-E and VEGF-A were found to possess similar bioactivities, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF-A, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentration, whilst in contrast to VEGF-A, VEGF-E did not bind to VEGF receptor-1 (Flt-1). VEGF-E is thus a potent angiogenic factor selectively binding to VEGF receptor-2. These data strongly indicate that activation of VEGF receptor-2 alone can efficiently stimulate angiogenesis.


Cyclic dibenzoylhydrazines reproducing the conformation of ecdysone agonists, RH-5849.
We have investigated the biologically active conformation of the non-steroidal ecdysone agonist, 1-tert-butyl-1,2-dibenzoylhydrazine (RH-5849) by means of design, synthesis and conformational analysis of cyclic derivatives of RH-5849. Among the synthesized compounds, a 6-membered cyclic hydrazine bearing two benzoyl groups (5) exists in three conformational states in solution, and the major unsymmetrical conformer of 5 is similar to that of RH-5849 on the basis of 1H NMR and X-ray analyses. The 3,3-dimethyl derivative of 5 (10) exists as a single unsymmetrical conformer. Although there is conformational similarity of the cyclic derivatives with RH-5849, these compounds did not show any hormonal or insecticidal activity. The hydrogen bonding character of the amide N-H group of the dibenzoylhydrazine seems to play a critical role in the appearance of the biological activity.


Chronology of medication errors by nurses: accumulation of stresses and PTSD symptoms.
The aim of this research was to examine the influence of medication errors on the mental state of the erring caregiver. In-depth interviews were conducted with 20 erring nurses. The data were analyzed using content analysis. The following categories were identified: "stress, pressure, and inattention," "responsibility," "the double fear," "I might get fired," "he who works, errs," waiting for the inquiry--"every day is like eternity," "absurdly, it got worse with time," and "following the event I learned my lessons." The emotional distress of several subjects was, across time, reminiscent of PTSD symptoms.


Stimulation in the NICU: is more necessarily better?
Animal studies and studies with human full-term infants suggest that the stimulation present in utero affects postnatal preferences and levels of response. The premature infant does not necessarily benefit from a re-creation of the in utero environment. Each aspect of the in utero environment should be assessed independently as a potential source of added stimulation in the NICU to determine its possible effects on the development of the premature infant. The NICU environment cannot be accurately labeled by global descriptors of "deprivation" or "overstimulation." When compared with the home environments of full-term infants from lower SES homes, different aspects of the NICU environment were recorded more often, less often, or equally as often as in the full-term infants' homes. Baseline levels of stimulation should be recorded in any NICU environment prior to the institution of an intervention program. NICU caregivers tended to respond contingently to their premature patients' behaviors. However, the prematures provided few opportunities for the nurses to respond, when visual and vocal behaviors used by full-term infants were employed as the expected norm. Perhaps both the medical staff and parents should be trained to recognize and respond to the more subtle, different cues described by Als et al. as being prevalent in the behavioral repertoire of the premature infant. Based on ecologic descriptions of NICU's, researchers have suggested that an inappropriate pattern of stimulation may characterize the environment, rather than an inappropriate amount of stimulation. The NICU environment has been characterized as providing little cross-modal stimulation, few temporally patterned stimuli, and little diurnal rhythmicity. In addition, the premature infant may have few opportunities to control the environment, contrary to the full-term infant's experiences. There is evidence of some negative effects of added NICU stimulation. Individual infants should be assessed prior to intervention for their level of behavioral maturation. Interventions should be individualized for the particular needs of each infant, rather than subjecting all infants assigned to a treatment condition with a stimulation "package." The worthy goal of promoting the development of premature infants carries with it the responsibility of ensuring that no harmful effects could befall any one infant.


Systematic review and meta-analysis of outcomes following pathological complete response to neoadjuvant chemoradiotherapy for rectal cancer.
Following neoadjuvant chemoradiotherapy (CRT) and interval proctectomy, 15-20 per cent of patients are found to have a pathological complete response (pCR) to combined multimodal therapy, but controversy persists about whether this yields a survival benefit. This systematic review evaluated current evidence regarding long-term oncological outcomes in patients found to have a pCR to neoadjuvant CRT. Three major databases (PubMed, MEDLINE and the Cochrane Library) were searched. The systematic review included all original articles reporting long-term outcomes in patients with rectal cancer who had a pCR to neoadjuvant CRT, published in English, from January 1950 to March 2011. A total of 724 studies were identified for screening. After applying inclusion and exclusion criteria, 16 studies involving 3363 patients (1263 with pCR and 2100 without) were included (mean age 60 years, 65·0 per cent men). Some 73·4 per cent had a sphincter-saving procedure. Mean follow-up was 55·5 (range 40-87) months. For patients with a pCR, the weighted mean local recurrence rate was 0·7 (range 0-2·6) per cent. Distant failure was observed in 8·7 per cent. Five-year overall and disease-free survival rates were 90·2 and 87·0 per cent respectively. Compared with non-responders, a pCR was associated with fewer local recurrences (odds ratio (OR) 0·25; P = 0·002) and less frequent distant failure (OR 0·23; P < 0·001), with a greater likelihood of being alive (OR 3·28; P = 0·001) and disease-free (OR 4·33, P < 0·001) at 5 years. A pCR following neoadjuvant CRT is associated with excellent long-term survival, with low rates of local recurrence and distant failure.


Quantitative analysis of triglycerides by high-performance liquid chromatography using non-linear gradient elution and flame ionization detection.
A high-performance liquid chromatographic (HPLC) technique using a commercial flame ionization detector for the analysis of triglyceride mixtures is described and discussed. A non-linear gradient elution programme giving a linear relationship between equivalent carbon numbers (ECNs) and retention times was developed. A new effect of chain length asymmetry on ECN values has been found.


Y chromosome STR haplotype data for an Irish population.
Y chromosome haplotype data was collected for 155 Irish males residing in the Republic of Ireland. Eleven short tandem repeat (STR) markers: DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 were analysed and the allele and haplotype frequencies calculated. This Irish data is presented here and was found to be less diverse when compared with the neighbouring UK population.


Fragmentation of molecular ions in differential mobility spectrometry as a method for identification of chemical warfare agents.
The subject of the work is the use of differential mobility spectrometry (DMS) for the detection of chemical warfare agents (CWA). Studies were performed for mustard gas, i.e., bis(2-chloroethyl)sulfide (HD), sarin, i.e., O-isopropyl methylphosphonofluoridate (GB) and methyl salicylate (MS) used as test compounds. Measurements were conducted with two ceramic DMS analyzers of different constructions allowing the generation of an electric field with an intensity of more than 120 Td. Detector signals were measured for positive and negative modes of operation in a temperature range from 0 to 80 °C. Fragmentations of ions containing analyte molecules were observed for all tested compounds. The effective temperatures of fragmentation estimated on the basis of dispersion plots were equal from about 148 °C for GB to 178 °C for MS. It was found that values of separation voltage (SV) and compensation voltage (CV) at which the fragmentation of sample ions is observed may be the parameters improving the certainty of detection for different analytes. The DMS analyzers enabling the observation of ion fragmentation can be successfully used for effective CWA detection.


The effect of cimetidine, phenobarbitone and buthionine sulphoximine on the disposition of N-5-dimethyl-9-[(2-methoxy-4-methyl-sulphonylamino)phenylamino]- 4-acridinecarboxamide (CI-921) in the rabbit.
N-5-dimethyl-9-[(2-methoxy-4-methylsulphonyl-amino)phenylamino]-4- acridinecarboxamide (CI-921) is an amsacrine analogue currently undergoing phase II clinical trials as an antitumor drug. Significant alterations in the plasma clearance (CL) of amsacrine have been demonstrated in rabbits after pretreatment with cimetidine (CT), phenobarbitone (PB) and buthionine sulphoximine (BSO). In the present study, the influence of these agents on the disposition of CI-921 was investigated in rabbits. After a short infusion of CI-921 (12.7 mumol/kg), blood (8 x 3 ml) was collected up to 12 h and the total plasma concentration of CI-921 determined by HPLC. Model-independent pharmacokinetic parameters were compared by Student's paired t-test. CT pretreatment significantly (P = 0.011) increased the AUC (mean, 21%; range, 3%-43%) and significantly (P = 0.019) decreased the CL (mean, 17%; range, 4%-30%). The induction effect of PB pretreatment was not confirmed with CI-921. No significant reduction in AUC or increase in CL was apparent. BSO pretreatment caused a small but significant (P = 0.049) increase in AUC (mean, 20.5%; range, 4%-59%) but had no effect on CL. Although more modest changes in kinetic parameters were observed with CI-921 than with amsacrine, these results suggested the involvement of the hepatic mixed-function oxidase system but not PB-inducible cytochrome P-450 isozymes in the elimination of CI-921 in the rabbit. As with amsacrine, a reduction in hepatic glutathione (GSH) concentrations in the body also appeared to have a modest effect on the disposition of CI-921.


Edible qualities, microbial compositions and volatile compounds in fresh fermented rice noodles fermented with different starter cultures.
To shorten the fermentation time and reduce the heterozygous bacteria contamination during fresh fermented rice noodles (FFRNs) fermentation, four starter cultures that consist of Limosilactobacillus fermentum, Lactoplantibacillus plantarum and Saccharomyces cerevisiae were used to produce FFRN. The cooking qualities and texture profiles of FFRNs, the dynamics of microbial diversities and volatile compounds at different fermentation stages were explored. Results showed that the fermentation time of the adding starter culture groups required 12 h, while that the natural fermentation (NF) group required 36 h. Significant differences were observed in the texture profiles and cooking qualities of these five groups FFRNs (P < 0.05). In addition, compared with NF group, the microbial diversity of four adding starter culture groups was significantly lower, which meant that the edible safety of FFRNs could be enhanced. Meanwhile, a total of 115 volatile compounds were detected by Gas chromatography-ion Mobility Spectrometry and Gas chromatography-mass spectrometry, the aldehydes, alcohols, acids and esters were increased while aldehydes were decreased in FFRNs during fermentation. Among these, the relative odor activity value of 50 volatile compounds was greater than 0.1, contributing unique flavors to FFRNs. Notably, the flavor of Lactoplantibacillus plantarum + Saccharomyces cerevisiae (L.p + S.c) and Lactoplantibacillus plantarum + Limosilactobacillus fermentum + Saccharomyces cerevisiae (L.pf + S.c) groups was richer than that of other groups.


Dinuclear Zinc Catalyzed Enantioselective Dearomatization [3+2] Annulation of 2-Nitrobenzofurans and 2-Nitrobenzothiophenes.
The application of dinuclear zinc catalysts in a dearomatization reaction has been developed. Catalytic asymmetric dearomatization [3+2] annulations of 2-nitrobenzofurans or 2-nitrobenzothiophenes with CF3 -containing N-unprotected isatin-derived azomethine ylides catalyzed by dinuclear zinc catalysts are realized with excellent diastereomer ratios (dr) of >20 : 1 and enantiomeric excess (ee) of up to 99 %. This protocol provides a practical, straightforward access to structurally diverse pyrrolidinyl spirooxindoles containing a 2,3-fused-dihydrobenzofuran (or dihydrobenzothiphene) moiety, and four contiguous stereocenters. Reactions can be performed on a gram scale. The absolute configuration of products is confirmed by X-ray single crystal structure analysis, and a possible mechanism is proposed.


Primary lymphoedema when found with distichiasis is of the type defined as bilateral hyperplasia by lymphography.
The occurrence of primary lymphoedema with distichiasis is well recognised, but that the form of lymphoedema appears restricted to bilateral hyperplasia, as defined by lymphography, has not been reported.


Morphometric analysis and functional correlation of tibial and femoral footprints in anatomical and single bundle reconstructions of the anterior cruciate ligament of the knee.
The anterior cruciate ligament (ACL) is composed of an infinite number of fibers whose individual anatomical and biomechanical features have been well defined. Although numerous biomechanical studies have shown that reconstruction that is as anatomical as possible results in better control of rotational laxity, very few studies have investigated the surface area of tibial and femoral insertion sites in these reconstructions. The aim of this study was to compare the surface areas of tibial and femoral insertion sites in single and double bundle reconstructions and correlate these findings with the isometry profile obtained. Our hypothesis was that double bundle (DB) reconstruction results in better filling of the native ACL footprint thus increasing the biomechanical value of available graft tissue. Forty-six patients underwent computer navigated ACL using hamstring tendons: 23 underwent single bundle (SB) and 23 DB reconstruction. The Praxim navigation station equipped with ACL logics software made it possible to digitize insertion site footprints, register perioperative data for graft position as well as anteroposterior and rotational laxities and pivot shift. There was a statistically significant difference between the two groups for tibial and femoral insertion site surface areas: 71 mm(2) ± 17 (SB) versus 99.9 mm(2) ± 30 (DB) for the tibia, 67 ± 11 mm(2) (SB) versus 96.9 mm(2) ± 28 (DB) for the femur. Isometry profiles showed that anisometry was favorable in all cases: 2.5 mm ± 2 for SB; 2.9 mm ± 2 for the anteromedial bundle (AMB) with DB and 9.6 mm ± 3.7 for the posterolateral bundle. When both groups were combined, there was a statistically significant correlation between the size of tibial insertion surface area and anteroposterior and rotational laxity. This study confirms that better filling of native ACL footprint surface areas results in better control of anteroposterior laxity. Level IV.


Effects of harman and norharman on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells.
The effects of harman and norharman on dopamine biosynthesis and L-DOPA-induced cytotoxicity in PC12 cells were investigated. Harman and norharman at a concentration of 20 microM and 100 microM showed 49.4% and 49.5% inhibition of dopamine content for 48 h, respectively. The IC50 values of harman and norharman were 21.2 microM and 103.3 microM. Dopamine content, tyrosine hydroxylase (TH) activity and TH mRNA levels were decreased during the first 6 h, maintained for up to 48 h and then gradually recovered at 72 h after exposure to 20 microM harman and 100 microM norharman. Under the same conditions, the intracellular cyclic AMP levels and Ca2+ concentrations were also decreased by harman and norharman. In addition, harman and norharman at concentrations higher than 80 microM and 150 microM caused cytotoxicity at 48 h in PC12 cells. Non-cytotoxic ranges of 10-30 microM harman and 50-150 microM norharman inhibited L-DOPA (20-50 microM)-induced increases in dopamine content at 48 h. Harman at 20-150 microM and norharman at 100-300 microM also enhanced L-DOPA (20-100 microM)-induced cytotoxicity at 48 h with an apoptotic process. These results suggest that harman and norharman inhibit dopamine biosynthesis by reducing TH activity and enhance L-DOPA-induced cytotoxicity in PC12 cells.


Pyrrolo[1,2-f]phenanthridines and related non-rigid analogues as antiviral agents.
The pyrrolo[1,2-f]phenanthridines 8-22 and the corresponding non-rigid analogues 23-41 were synthesised and their ability to inhibit the replication of HIV-1 was tested. Only the polycyclic derivatives 10, 11, and 13 showed a weak anti-HIV activity, whereas several pyrrolo-phenanthridines (8, 10, 16-18) were found to stimulate the multiplication of MT-4 cells at low concentrations. Derivative 10 demonstrated to possess the unique property of stimulating the multiplication of lymphocytes joined to HIV inhibition.


Faim knockout leads to gliosis and late-onset neurodegeneration of photoreceptors in the mouse retina.
Fas Apoptotic Inhibitory Molecule protein (FAIM) is a death receptor antagonist and an apoptosis regulator. It encodes two isoforms, namely FAIM-S (short) and FAIM-L (long), both with significant neuronal functions. FAIM-S, which is ubiquitously expressed, is involved in neurite outgrowth. In contrast, FAIM-L is expressed only in neurons and it protects them from cell death. Interestingly, FAIM-L is downregulated in patients and mouse models of Alzheimer's disease before the onset of neurodegeneration, and Faim transcript levels are decreased in mouse models of retinal degeneration. However, few studies have addressed the role of FAIM in the central nervous system, yet alone the retina. The retina is a highly specialized tissue, and its degeneration has proved to precede pathological mechanisms of neurodegenerative diseases. Here we describe that Faim depletion in mice damages the retina persistently and leads to late-onset photoreceptor death in older mice. Immunohistochemical analyses showed that Faim knockout (Faim-/- ) mice present ubiquitinated aggregates throughout the retina from early ages. Moreover, retinal cells released stress signals that can signal to Müller cells, as shown by immunofluorescence and qRT-PCR. Müller cells monitor retinal homeostasis and trigger a gliotic response in Faim-/- mice that becomes pathogenic when sustained. In this regard, we observed pronounced vascular leakage at later ages, which may be caused by persistent inflammation. These results suggest that FAIM is an important player in the maintenance of retinal homeostasis, and they support the premise that FAIM is a plausible early marker for late photoreceptor and neuronal degeneration.


Helicobacter pylori genotype and polymorphisms in DNA repair enzymes: where do they correlate in gastric cancer?
One of the mechanisms proposed by which H. pylori causes gastric cancer (GC) is through DNA damage due to chronic inflammation. Genomic integrity is guaranteed by repair enzymes such as APE-1, OGG-1, and PARP-1. Host genetic polymorphisms associated with the bacterial strain may influence the ability to repair the damage, contributing to the development of H. pylori-associated GC. The aim of this study was to determine the association of the polymorphisms APE-1 (T2197G), OGG-1 (C1245G), and PARP-1 (A40676G) with H. pylori-genotype in 109 patients with GC. Polymorphism was assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and H. pylori detection/genotyping by PCR. In the intestinal subtype, PARP-1 wild-type was more frequent (P=0.001) in patients >50 years old. The repair enzymes genotypes analyzed in combination showed that the less pathogenic strains are associated with the APE-1 polymorphic allele and, unexpectedly, with PARP-1 wild-type, but this last one associated with APE-1 polymorphic allele or in older patients. Our results indicate the importance of H. pylori and APE-1 genotypes in the gastric carcinogenesis. Also, support the hypothesis of a decrease of PARP-1 wild-type activity in older individuals. Taken together these data may be an important clue to understand the role of low-virulence strains of H. pylori in gastric carcinogenesis and point the importance to analyze the polymorphisms as a group.


[Circadian changes of various enzyme activities in the kidney macula densa of gerbils (Meriones unguiculati)].
Circadian Changes of the Activity of some Enzymes in the Macula densa of the Kidney of Mongolian Gerbilis.--The authors investigated the enzyme histochemical activity of some dehydrogenases in the macula densa of desert rodents killed respectively at 11 a.m. and at 11 p.m. The percentage of macula cells which, in comparison with the non specific distal convolution epithelial cells, showed the same or even enhanced enzyme activities was higher at 11 p. m., i.e. nightly (see Tab. 1).


Danon Disease: Entire LAMP2 Gene Deletion with Unusual Clinical Presentation-Case Report and Review of the Literature.
Danon disease is a rare x-linked dominant multisystemic disorder with a clinical triad of severe cardiomyopathy, skeletal myopathy, and intellectual disability. It is caused by defects in the lysosome-associated membrane protein-2 (LAMP2) gene. Numerous different mutations in the LAMP2 protein have been described. Danon disease is typically lethal by the mid-twenties in male patients due to cardiomyopathy and heart failure. Female patients usually present with milder and variable symptoms. This report describes a 42-year-old father and his 3-year-old daughter presenting with mild manifestations of the disease. The father has normal intellectual development and normal physical activity. At the age of 13, he was diagnosed with mild ventricular pre-excitation known as Wolf-Parkinson-White syndrome (WPWs), very mild and mostly asymptomatic cardiomyopathy and left ventricular hypertrophy, and at about the age of 25 presented with visual impairment due to cone-rod dystrophy. His daughter showed normal development and very mild asymptomatic electrocardiographic WPWs abnormalities with left mild ventricular hypertrophy. Genetic testing revealed an Xq24 microdeletion encompassing the entire LAMP2 gene. Relevant literature was reviewed as a reference for the etiology, diagnosis, treatment and case management.


Electrochemical sensor for bisphenol A based on magnetic nanoparticles decorated reduced graphene oxide.
Bisphenol A (BPA), as one kind of endocrine-disrupting chemicals, has adverse impact on human health and environment. It is urgent to develop effective and simple methods for quantitative determination of BPA. In this work, an electrochemical sensor for BPA based on magnetic nanoparticles (MNPs)-reduced graphene oxide (rGO) composites and chitosan was presented for the first time. The MNPs-rGO composites were characterized by scanning electron microscopy, X-Ray diffraction and Fourier transform infrared spectroscopy. Electrochemical studies show that MNPs-rGO composites can lower the oxidation overpotential and enhance electrochemical response of BPA due to the synergetic effects of MNPs and rGO. Under the optimal experiment conditions, the oxidation peak current was proportional to the concentration of BPA over the range of 6.0×10(-8) to 1.1×10(-5)molL(-1) with the detection limit of 1.7×10(-8)molL(-1). Moreover, the MNPs-rGO based electrochemical sensor shows excellent stability, reproducibility and selectivity. The electrochemical sensor has been successfully applied to the determination of BPA in real samples with satisfactory results.


Structural requirements of organophosphorus insecticides (OPI) to inhibit chicken yolk sac membrane kynurenine formamidase related to OPI teratogenesis.
This paper provides new information related to the mechanism of OPI (organophosphorus insecticides) teratogenesis. The COMFA (comparative molecular field analysis) and COMSIA (comparative molecular similarity indices analysis) suggest that the electrostatic and steric fields are the best predictors of OPI structural requirements to inhibit in ovo chicken embryo yolk sac membrane kynurenine formamidase, the proposed target for OPI teratogens. The dominant electrostatic interactions are localized at nitrogen-1, nitrogen-3, nitrogen of 2-amino substituent of the pyrimidinyl of pyrimidinyl phosphorothioates, and the oxygen of crotonamide carbonyl in crotonamide phosphates. Bulkiness of the substituents at carbon-2 and carbon-6 of the pyrimidinyls and/or N-substituents and carbon-3 substituents of crotonamides are the steric structural components that contribute to superiority of those OPI as in ovo inhibitors of kynurenine formamidase.


Gap junction blockade does not alter eupnea or gasping in the juvenile rat.
The role of gap junctions in the brainstem respiratory control system is ambiguous. In the present study, we used juvenile rats to determine whether blocking gap junctions altered eupnea or gasping in the in situ, arterially perfused rat preparation. Blockade of gap junctions with 100 microM carbenoxolone or 300 microM octanol did not produce any consistent changes in the timing or amplitude of integrated phrenic discharge or in the peak frequency in the power spectrum of phrenic nerve discharge during eupnea or ischemic gasping beyond those changes seen in time-control animals. These findings do not rule out a role for gap junctions in the expression of eupnea or gasping, but they do demonstrate that these intermembrane channels are not obligatory for either rhythm to occur.


A Novel Finger Illusion Reveals Reduced Weighting of Bimanual Hand Cortical Representations in People With Complex Regional Pain Syndrome.
Complex regional pain syndrome (CRPS) is associated with deficits in sensorimotor control. Herein we have used a novel finger illusion to investigate whether CRPS is associated with reduced weighting of bimanual hand representations. The illusion normally induces a compelling feeling that the hands are close together when in fact they are 12 cm apart. People with CRPS and age, gender, and dominant hand-matched controls tested the illusion in the midline then on either side of the midline. The illusion had 2 variants; the passive pincer-grip position, without contact (no grasp condition) and with contact (grasp condition) of the artificial finger. The primary outcome was the perceived vertical distance between the index fingers. Twenty people with CRPS and 20 controls participated (mean age 44.4 ± 11.7 years). During the no grasp condition, participants with CRPS perceived the vertical distance significantly closer to the actual 12 cm (mean 8.0 cm, 95% confidence interval 6.5-9.5 cm), than controls did (mean 6.4 cm, 95% confidence interval 5.5-7.2 cm]). That is, the illusion was weaker in people with CRPS than in controls during no grasp. There was no such difference during grasp; that is, both groups showed the predicted illusion response. There was no effect of hand placement relative to midline or relative to the opposite hand. We conclude that people with unilateral CRPS have lower weighting of bimanual hand representation than controls have, independent of hand location. However, adding additional cutaneous input returns those with CRPS to the expected performance. We suggest the results have clear clinical and research implications. PERSPECTIVE: An abnormal weighting of bilateral hand representation may reflect a vulnerability for chronic CRPS, an adaptation to the disease, and/or a potential therapeutic target. That addition of cutaneous input immediately normalizes the problem points to the possible role of bimanual tasks in prevention or rehabilitation.


Food, Medicine, and Function: Food Is Medicine Part 1.
Food is not just calories; food is information. Food is a complex array of macronutrients, vitamins, minerals, and phytochemicals that upgrade or downgrade our biological software with every bite. The standard American diet lacks essential nutrients and is rich in refined flour, sugar, and inflammatory oils that drive dysbiosis, metabolic dysfunction, and chronic disease. Modern medicine focuses on diagnosing and treating disease with drugs, not creating health. Functional medicine organizes the body into a network of interconnected systems. It focuses on correcting the underlying functional imbalances that drive disease while restoring health using personalized diet, lifestyle, and nutrition interventions.


De novo FUS gene mutations are associated with juvenile-onset sporadic amyotrophic lateral sclerosis in China.
Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of motor neuron disease and occurs before 25 years of age. Only very few sporadic cases of juvenile-onset ALS have been reported. Rare SOD1 mutations and several FUS mutations have been identified in juvenile-onset ALS patients. To define the genetics of juvenile-onset sporadic ALS (SALS) of Chinese origin, we sequenced all 5 exons of SOD1, exons 3-6 and 12-15 of FUS in 11 juvenile-onset SALS patients, 105 adult-onset ALS patients (including 6 familial ALS [FALS] pedigrees), and 245 healthy controls. For the 11 juvenile-onset SALS and 6 FALS cases, the other 7 exons of FUS were also screened. A heterozygous de novo missense mutation c.1574C>T (p.P525L), a heterozygous de novo 2-base pair deletion c.1509_1510delAG (p.G504Wfs*12), and a nonsense mutation c.1483C>T (p.R495X) was each identified in 1 juvenile SALS patient. A heterozygous missense mutation c.1561C>G (p.R521G) was identified in a FALS proband. In the Chinese population, the frequency of FUS mutation in FALS is 11.4% (95% confidence interval [CI], 0.9%-22.0%), higher than the Japanese (10%; 95% CI, 0.7%-19.3%), and Caucasians (4.9%; 95% CI, 3.9%-6.0%). The frequency of FUS mutation in SALS patients is 1.5% (95% CI, 0.2%-2.9%), which is similar to Koreans (1.6%; 95% CI, 0%-3.2%), but higher than in Caucasians (0.6%; 95% CI, 0.4%-0.8%). Our findings suggest that de novo FUS mutations are associated with juvenile-onset SALS of Chinese origin and that this gene should be screened in ALS patients with a young age of onset, aggressive progression, and sporadic occurrence.


Meta-analysis comparing outcomes of catheter ablation for ventricular arrhythmia in ischemic versus nonischemic cardiomyopathy.
Catheter ablation is an effective treatment for ventricular arrhythmia (VA) in ischemic cardiomyopathy (ICM). However, results in non-ICM (NICM) patients are not satisfactory, and studies comparing differences between NICM and ICM are limited. We conducted a meta-analysis of procedural characteristics and long-term outcomes of catheter ablation for VA, comparing results between ICM and NICM. Studies in the PubMed, EMBASE, and Cochrane databases were systematically reviewed. Four studies reporting comparison of catheter ablation of VA between ICM and NICM were examined. The Newcastle-Ottawa Scale was used to appraise study quality. A random-effects model with inverse variance method was used for comparisons. Epicardial approach was significantly more undertaken for the NICM group than in the ICM group (odds ratio [OR]: 0.13; 95% confidence interval [CI]: 0.09-0.18; P < .00001). Mean ablation time (P = .54), fluoroscopy time (P = .55), and procedural time (P = .18) did not differ significantly between the ICM and NICM groups. Procedural failure rates (OR: 0.46; 95% CI: 0.24-0.89; P = .02) and VA recurrence rates (risk ratio [RR]: 0.68; 95% CI: 0.46-1.01; P = .06) were significantly higher in the NICM group than in the ICM group. However, all-cause mortality (RR: 1.37; 95% CI: 0.75-2.49; P = .31) did not differ significantly between groups. Procedural failure and VA recurrence rates were significantly higher in the NICM group, despite significantly more frequent epicardial access. These highlight the limitations of catheter ablation for VA in NICM, given our current knowledge.


5-HT3 receptors mediate rapid responses in cultured hippocampus and a clonal cell line.
Serotonin (5-HT) induces a large inward current accompanied by a conductance increase when applied focally to either neurons of mouse hippocampal cultures or cells of the NG108-15 clonal cell line. In both systems, the response is blocked by ICS 205-930, curare, and metoclopramide, while 2-methyl-5-HT is an agonist. The actions of ICS 205-930 and 2-methyl-5-HT indicate that the response is mediated by the 5-HT3 receptor. In NG108-15 cells the response activated in as little as 35 ms. The rapidity of the response suggests a direct coupling between the 5-HT3 receptor and a channel, which are probably both part of a single membrane protein. In both cell types, prolonged application of 5-HT resulted in desensitization; the rates of desensitization were accelerated by the adenylate cyclase activator forskolin. The 5-HT3 receptor has much in common with the nicotinic receptor and is probably involved in rapid synaptic transmission in the mammalian brain. Since this response is modulated by manipulations that elevate intracellular cAMP levels, the central synapses in which this receptor operates may exhibit plasticity.


5-HT2 and 5-HT2B antagonists attenuate pro-fibrotic phenotype in human adult dermal fibroblasts by blocking TGF-β1 induced non-canonical signaling pathways including STAT3 : implications for fibrotic diseases like scleroderma.
Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-β1)-dependent manner. To evaluate anti-fibrotic properties of inhibitors of 5-HT2 and 5-HT2B (terguride, SB204741) respectively in human adult dermal fibroblasts (HADF) derived from a patient with scleroderma. Anti-fibrotic efficacy of 5-HT2 and 5-HT2B inhibitors was evaluated as per two strategies: HADF were incubated with 5-HT (1 μM)/TGF-β1 (10 ng/mL) for 1 hour followed by 5-HT (1 μM)/TGF-β1 (10 ng/mL) and terguride or SB204741 (1 μM, each) for 24 hours (post-treatment strategy) and HADF were treated with terguride or SB204741 (1 μM, each) for 1 hour followed by 5-HT (1 μM)/TGF-β1 (10 ng/mL) for 24 hours (pre-treatment strategy). Real time quantitative polymerase chain reaction for expression of pro-fibrotic (TGFΒ1, COL1A1, COL1A2, ACTA2, CTGF and FN1) and anti-fibrotic genes (MMP2/TIMP1) was performed. Expression of type I collagen, alpha smooth muscle actin (α-SMA), phosphorylation of Smad3, ERK1/2 and STAT3 was examined by immunoblotting. Stimulation of HADF cells with 5-HT/TGF-β1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-β1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation. Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-β1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.


Significance of epidermal growth factor receptor expression in primary human endometrial cancer.
Radioreceptorial assessment of EGFR expression was prospectively performed on 60 primary human endometrial tumors. Of these, 26 were EGFR-positive while 13 expressed high EGFR levels. High EGFR levels correlated well with poor histopathological grading. No correlation with histopathological type, stage, myometrial invasion, lymph-node involvement or steroid hormone receptor status was observed. Disease-free survival rate was significantly shorter in the cases with high than in the cases with low EGFR levels. These results suggest a potential role of EGFR expression assessment in prognostic characterization of endometrial cancer patients.


A kinetic study of the effects of phosphate and organic phosphates on the activity of phosphoenolpyruvate carboxylase from Crassula argentea.
The effects of phosphate and several phosphate-containing compounds on the activity of purified phosphoenolpyruvate carboxylase (PEPC) from the crassulacean acid metabolism plant, Crassula argentea, were investigated. When assayed at subsaturating phosphoenolpyruvate (PEP) concentrations, low concentrations of most of the compounds tested were found to stimulate PEPC activity. This activation, variable in extent, was found in all cases to be competitive with glucose 6-phosphate (Glc-6-P) stimulation, suggesting that these effectors bind to the Glc-6-P site. At higher concentrations, depending upon the effector molecule studied, deactivation, inhibition, or no response was observed. More detailed studies were performed with Glc-6-P, AMP, phosphoglycolate, and phosphate. AMP had previously been shown to be a specific ligand for the Glc-6-P site. The main effect of Glc-6-P and AMP on the kinetic parameters was to decrease the apparent Km and increase Vmax/Km. AMP also caused a decrease in the Vmax of the reaction. In contrast, phosphoglycolate acted essentially as a competitive inhibitor increasing the apparent Km for PEP and decreasing Vmax/Km. Inorganic phosphate had a biphasic effect on the kinetic parameters, resulting in a transient decrease in Km followed by an increase of the apparent Km for PEP with increasing concentration of phosphate. The Vmax also was decreased with increasing phosphate concentrations. Further, the enzyme appeared to respond to the complex of phosphate with magnesium. In the presence of a saturating concentration of AMP, no activation but rather inhibition was observed with increasing phosphate concentration. This is consistent with the binding of phosphate to two separate sites--the Glc-6-P activation site and an inhibitory site, a phenomenon that may be occurring with other phosphate containing compounds. High concentrations of phosphate with magnesium were found to protect enzyme activity when PEPC, previously shown to contain an essential arginine at the active site, was incubated with the specific arginyl reagent 2,3-butanedione, consistent with the binding of phosphate at the active site. Data were successfully fitted to a rapid equilibrium model allowing for binding of the phosphate-magnesium complex to both the activation site and the active site which accounts for the activation/deactivation observed at low substrate concentrations. Effects on the Vmax of the reaction are also addressed. Factors controlling the differential affinity of various effectors to the active site or activation site appear to include charge distribution, size, and other steric factors.


Correction to: Abstracts from the 5th International Porto Congress of Multiple Sclerosis.
The given name of one of the authors was incorrectly published as Vera in abstract EPIII028 "Anti-MOG Antibody-Positive Isolated Longitudinally Extensive Transverse Myelitis". The correct name should read as follows.


Red narrow-linewidth lasing and frequency comb from gain-switched self-injection-locked Fabry-Pérot laser diode.
Narrow-linewidth lasers are in extensive demand for numerous cutting-edge applications. Such lasers operating at the visible range are of particular interest. Self-injection locking of a laser diode frequency to a high-Q whispering gallery mode is an effective and universal way to achieve superior laser performance. We demonstrate ultranarrow lasing with less than 10 Hz instantaneous linewidth for 20 [Formula: see text]s averaging time at 638 nm using a Fabry-Pérot laser diode locked to a crystalline MgF[Formula: see text] microresonator. The linewidth measured with a [Formula: see text]-separation line technique that characterizes 10 ms stability is as low as 1.4 kHz. Output power exceeds 80 mW. Demonstrated results are among the best for visible-range lasers in terms of linewidth combined with solid output power. We additionally report the first demonstration of a gain-switched regime for such stabilized Fabry-Pérot laser diode showing a high-contrast visible frequency comb generation. Tunable linespacing from 10 MHz to 3.8 GHz is observed. We demonstrated that the beatnote between the lines has sub-Hz linewidth and experiences spectral purification in the self-injection locking regime. This result might be of special importance for spectroscopy in the visible range.


[Surgical approach to the shoulder. Lesser tuberosity osteotomy].
Osteotomy of the lesser tuberosity for the surgical delto-pectoral approach to the glenohumeral joint results in good visualization and overview and sufficient anatomical refixation of the insertion of the subscapularis muscle. However, clinical and biomechanical studies have not shown clearly significantly better results for osteotomy concerning ultimate load to failure, displacement after cyclic loading and outcome in patients compared with tenotomy and tenodesis of the subscapularis tendon. One advantage of osteotomy, however, is the potential radiological evaluation of the refixation with healing of the bony fragment. In the context of refixation, securing of the sutures behind the stem during implantation can be beneficial because it prevents sutures cutting through the bone. This benefit is increased in cemented stems by means of better suture fixation. With respect to the choice of osteotomy or tenotomy, the bony substance and tendon quality of the insertion of the subscapularis muscle should be evaluated.


Detection of changes in avian influenza genome fragments by multitemperature single-strand conformational polymorphism.
We have applied the temperature-dependent single-stranded conformational polymorphism (SSCP) analysis for characterization of influenza A virus cDNA fragments. A series of primers were synthesized on the basis of the comparison of hemagglutinin and PB2 gene sequences of different origin. RT-PCR reactions were run using these primers, products were denatured and single-strand DNA fragments were subjected to electrophoresis. After silver staining, ssDNA band patterns characteristic for each genotype were observed. Minor differences within a serotype were detected without need for sequencing the PCR products making the preliminary analysis of avian influenza isolates much faster.


The successful medical management of severe duodenal strictures secondary to eosinophilic gastroenteritis in an infant.
Eosinophilic gastroenteritis is an uncommon condition of unknown etiology that has only been relatively recently reported. Its clinical manifestations range from a mild disease to more severe forms resembling Crohn's disease. Enteric strictures are a rare but recognized complication of this condition. We report a case of eosinophilic gastroenteritis in an infant presenting with severe duodenal strictures that was successfully managed with oral prednisolone. We believe that this is the first reported case of duodenal strictures secondary to eosinophilic gastroenteritis.


The clinical significance of metabolic syndrome in hypertension: metabolic syndrome increases cardiovascular risk : the pro position.
Changes in lifestyle in the developed world are promoting the epidemic growth of overweight and obesity, leading to several metabolic abnormalities (lipids, glucose and blood pressure), and increasing the future risk of type 2 diabetes mellitus, cardiovascular events and death. Metabolic syndrome represents the combination of abdominal obesity, insulin resistance, atherogenic dyslipidaemia, and prothrombotic and proinflammatory states. Although some controversies in the pathogenesis and clinical importance of metabolic syndrome still remain, the development of useful clinical tools to identify these patients more easily has enabled an increased recognition in the adult population. Management of patients with metabolic syndrome is a clinical challenge and requires a multifactorial, multidisciplinary approach. Changes in lifestyle are obviously the first therapeutic step and include both dietary modifications and increased daily exercise. Several questions remain to be elucidated with respect to pharmacological treatment. The blood pressure levels required to initiate antihypertensive treatment, the blood pressure goal to be achieved and the possibility of including a renin-angiotensin system blocker as a part of the pharmacological treatment are still under discussion. Moreover, there is either a lack of or poor evidence on the need for specific drugs to reduce triglycerides, to increase high-density lipoprotein-cholesterol, to improve insulin sensitivity or to decrease abdominal obesity. Independently, it is generally accepted that earlier and more aggressive therapy in subjects with metabolic syndrome will result in a future decrease in cardiovascular morbidity and mortality worldwide.


Downregulation of microRNA-214 and overexpression of FGFR-1 contribute to hepatocellular carcinoma metastasis.
miR-214 is one of the most significantly downregulated microRNAs (miRNAs) in hepatocellular carcinoma (HCC). Fibroblast growth factor receptor 1 (FGFR-1) is a miR-214 target gene implicated in the progression of HCC. However, the roles of miR-214 and FGFR-1 in HCC are not fully understood. Here, we analyzed the expression of miR-214 and FGFR-1 in 65 cases of HCC and paired non-neoplastic tissue specimens using real-time PCR and Western blot (WB), respectively. Our data indicated that miR-214 was downregulated and FGFR-1 was overexpressed in HCC compared to the paired non-neoplastic tissues. The low miR-214 expression was correlated with portal vein invasion (p=0.016) and early recurrence (p=0.045) in HCC patients. Moreover, the low miR-214 expression was correlated with high positive rate of FGFR-1 in HCC cases (p=0.020). Our data further demonstrated that miR-214 overexpression in SK-HEP1 and HepG2 cells downregulated FGFR-1 expression and inhibited liver cancer cell invasion. The Luciferase assay results further demonstrated the targeted regulation of FGFR-1 by miR-214. In conclusion, our data indicate that the downregulation of miR-214 in HCC and the upregulation of its target gene FGFR-1 is associated with HCC progression. Therefore, miR-214 and FGFR-1 are potential prognostic markers and therapeutic targets in HCC.


Frequency and type of toenail tumors in the dromedary camel.
A total of 275 dromedary camels (16 males and 259 females) of local "Arabiyat" breed suffering from different types and degrees of severity of toenail tumors were surgically treated. Histopathological examination of the tissue samples removed from 50 tumor-like growths (2 males and 48 females) revealed three types of tumors; squamous cell carcinoma (70%), spiny keratoderma (22%) and fibroma (8%). An increased incidence of tumors was recorded in the medial when compared to the lateral toenails in both sexes. In females, the incidence in the medial toenails was 90/259 (34.75%) and 71/259 (27.41%) in the right and left forelimbs respectively when compared to the lateral toenails which was 25/259 (9.65%) and 5/259 (1.93%) for the respective right and left forelimbs. In the hind limbs, this ratio was 29/259 (11.20%) and 20/259 (7.72%) for right and left medial toenails respectively, whereas it was 17/259 (6.56%) and 2/259 (0.77%) for the right and left lateral toenails respectively. Similar to the observations in female camels, male camels also showed a higher incidence of these tumors in the medial when compared to the lateral toenails in both fore and hind limbs. Based on these findings, we conclude that in the dromedary camels, the medial toenails of the fore limbs are most commonly affected with tumors; with the most common tumor being the squamous cell carcinoma.


Maternal hypomagnesemia causes placental abnormalities and fetal and postnatal mortality.
Magnesium (Mg(2+)) is essential for cellular growth and the maintenance of normal cellular processes. However, little is known about how maternal hypomagnesemia during pregnancy affects fetal growth and development. This study investigated the effects of maternal hypomagnesemia on the late gestation placenta and fetus, and postnatal outcomes until weaning. Female CD1 mice consumed a control (0.2% w/w Mg(2+)), moderately Mg(2+) deficient (MMD; 0.02% w/w Mg(2+)) or severely Mg(2+) deficient (SMD; 0.005% w/w Mg(2+)) diet for 4 weeks prior to mating and throughout pregnancy. Dams were killed at E18.5 for embryonic studies or allowed to litter naturally and the offspring studied up to postnatal day 21. At E18.5, both Mg(2+) deficient diets decreased maternal plasma and bone Mg(2+) but only the SMD diet decreased fetal plasma Mg(2+). Maternal hypomagnesemia led to fetal loss and fetal growth restriction. Maternal Mg(2+) deficiency increased placental glycogen cell area and decreased spongiotrophoblast cell area while upregulating mRNA expression of the MagT1 Mg(2+) transporter in spongiotrophoblast cells. The SMD animals also displayed instances of gross placental abnormalities. After birth, pups in the SMD group had increased early postnatal mortality and failed to thrive. Pups in the MMD group underwent catch-up growth but remained shorter than controls at PN21 and were hypomagnesemic and hypoglycemic. These changes suggest that maternal Mg(2+) deficiency during pregnancy impairs placental development and fetal growth, which may have long-term health consequences for offspring. Collectively, these results have important implications for women who are Mg(2+) deficient during pregnancy.


Anatomic characteristics of ventricular septal defect associated with coarctation of the aorta.
The morphologic characteristics of ventricular septal defect (VSD) and left ventricular outflow tract were studied in 45 hearts with VSD and coarctation of the aorta (C of A). Forty-one VSDs were classified into 1 of 4 categories. The first category includes 19 central muscular VSDs (43%), among which 3 hearts had the architecture of a spontaneously closed defect. The second category includes 10 perimembranous inlet defects (23%) with overlying tricuspid valve. The third category is formed by 8 perimembranous VSDs with leftward outlet septal malalignment (18%) and the fourth category includes 4 subarterial VSDs (8%) in which leftward malalignment of a deficient outlet septum results in subpulmonary localization of the defect. In addition to the main categories, 1 membranous, 1 perimembranous trabecular, 1 apical muscular and 1 doubly committed subarterial defects were identified. The left ventricular outflow tract was assessed as normal in only 2 cases. In 43 cases the left ventricular outflow tract was compromised by 1 or more of the following anomalies: anterolateral muscle bundle, anteroseptal twist, bicuspid aortic valve or a leftward malaligned outlet septum. These findings support the hypothesis of C of A being hemodynamically induced by anomalies of the left ventricular outflow tract. Previous studies have established that muscular, membranous and perimembranous inlet defects are prone to close spontaneously, in contrast to malalignment and subarterial VSDs. The present study shows that 70% of the VSDs belong to types characterized by a high incidence of spontaneous closure.


Structural insight into the interactions of SoxV, SoxW and SoxS in the process of transport of reductants during sulfur oxidation by the novel global sulfur oxidation reaction cycle.
Microbial redox reactions involving inorganic sulfur compounds, mainly the sulfur anions, are one of the vital reactions responsible for the environmental sulfur balance. These reactions are mediated by phylogenetically diverse prokaryotes, some of which also take part in the extraction of metal ions from their sulfur containing ores. These sulfur oxidizers oxidize inorganic sulfur compounds like sulfide, thiosulfate etc. to produce reductants that are used for carbon dioxide fixation or in respiratory electron transfer chains. The sulfur oxidizing gene cluster (sox) of alpha-Proteobacteria comprises of at least 15 genes, forming two transcriptional units, viz., soxSR and soxVWXYZABCDEFGH. SoxV is known to be a CcdA homolog involved in the transport of reductants from cytoplasm to periplasm. SoxW and SoxS are periplasmic thioredoxins, which (SoxW) interact with SoxV and thereby help in the redox reactions. We have employed homology modeling to construct the three-dimensional structures of the SoxV, SoxW and SoxS proteins from Rhodovulum sulfidophilum. With the help of docking and molecular dynamics simulations we have identified the amino acid residues of these proteins involved in the interaction. The probable biochemical mechanism of the transport of reductants through the interactions of these proteins has also been investigated. Our study provides a rational basis to interpret the molecular mechanism of the biochemistry of sulfur anion oxidation reactions by these ecologically important organisms.


Neural responses to acute cocaine administration in the human brain detected by fMRI.
An improved functional MRI (fMRI) method for the reduction of susceptibility artifacts has been utilized to measure blood oxygen level-dependent (BOLD) responses to acute cocaine administration in the human brain of cocaine users. Intravenous administration of cocaine (20 mg/70 kg) activated mesolimbic and mesocortical dopaminergic projection regions and showed temporal positive or negative BOLD responses. These results obtained from human cocaine users supported the involvement of the dopaminergic pathway in cocaine addiction from animal models. In addition, the cocaine administration also induced activations in the hierarchical brain networks in the anterior prefrontal cortex (aPFC) of the Brodmann area 10 (BA10) and orbitofrontal cortex (OFC). It is suggested that the dopaminergic pathways and the hierarchical brain networks may participate in mediating cocaine reward processes, associative learning, motivation, and memory in cocaine addiction in the human brain.


Numerical and functional response of predators to a long-term decline in mammalian prey at a semi-arid Neotropical site.
Occurrence and diet of ten carnivorous predators (four falconiforms, four owls, and two foxes), and population levels of their mammalian prey, were monitored over 45 months at a semi-arid site in north-central Chile. Early in this period, small mammals irrupted and then declined markedly to a density 7% of that at peak. All four falconiforms (Buteo polyosoma, Falco sparverius, Geranoaetus melanoleucus, Parabuteo unicinctus) and one owl (Tyto alba) responded numerically to the decline in mammalian prey by virtually abandoning the study site. The three other owls (Athene cunicularia, Bubo virginianus, Glaucidium nanum) and the two foxes (Pseudalopex culpaeus and P. griseus) remained. With few exceptions, throughout the study predators maintained species-specific preferences among small mammal species regardless of the absolute and proportional abundance of these prev. At no time did the two prey species most responsible for the irruption (the rodents Phyllotis darwini and Akodon olivaceus) occur in predators' diets out of proportion to their estimated relative abundance in the field. Predators were clearly unable to prevent the irruption from occurring. Given the absence of a clear functional response to the most irruptive species, predators seemed unlikely to have been responsible for the observed crash. At present, however, predators may be prolonging the crash and delaying the return of small-mammal populations to typical densities.


Danggui Sini Decoction (herbal medicine) for the treatment of primary dysmenorrhoea: a systematic review and meta-analysis.
Danggui Sini Decoction (DSD), a traditional herbal prescription, has been commonly used in the treatment of primary dysmenorrhoea (PD). We investigated the current evidence of randomised controlled trials (RCTs) and performed a systematic review to evaluate the efficacy of DSD in the treatment of PD. We registered the protocol for this systemic review in PROSPERO with the registration number CRD 42017074062 on August 10, 2017. Nine databases were searched from inception to August 2019. Eleven RCTs with 1005 patients were included. DSD was shown to have more favourable effects on the clinical effective rate than western medicine, which support the clinical use of DSD in the treatment of PD. However, considering the high risk of bias in the included studies, more well-designed RCTs are needed to further evaluate the efficacy of DSD in the treatment of PD.


A novel very small granular starch from Chlorella sp. MBFJNU-17.
Novel resources of very small granular starch are of great interests to food scientists. We previously found Chlorella sp. MBFJNU-17 contained small granular starch but whether the MBFJNU-17 was a novel resource of very small granular starch remained unresolved. This study isolated and characterized the starch from MBFJNU-17 in comparison with quinoa starch (a typical very small granular starch), and discussed whether the MBFJNU-17 could be a resource of very small granular starch. Results showed that chlorella starch displayed a smaller size (1024 nm) than quinoa starch did (1107 nm), suggesting MBFJNU-17 was a good resource of very small granular starch. Additionally, chlorella starch had less amylose, higher proportion of long amylopectin branches, more ordered structures, thinner amorphous lamellae, better paste thermostability, and slower enzymatic digestion than quinoa starch did. These findings indicated that Chlorella sp. MBFJNU-17 was a novel resource of very small granular starch with desirable thermostability and nutritional attributes.


Cooperative organization in a macromolecular complex.
The mechanism of assembly of multiprotein complexes and the subsequent organization of activity are not well understood. Here we report the application of biophysical tools to investigate the relationship between structure and function in protein assemblies. We used as a model system the SCF(Skp2) complex that targets p27(Kip1) for ubiquitination and subsequent degradation; this process requires an adapter protein, Cks1. By dissecting the interactions between the different subunits we show that the properties of Cks1 are highly context dependent, and its activity is acquired only when the complex is fully assembled. The results provide insights into the central role of small adapters in macromolecular assembly and explain their high sequence conservation. Simultaneous and synergistic binding of multiple subunits in a complex provides the specificity and control required before the key cell-cycle regulator p27 is committed to degradation.


Retinoblastoma mutation rate in New Zealand and support for the two-hit model.
Age-specific incidence rates for 96 New Zealand patients with sporadic retinoblastoma peaked earlier for bilateral patients than for unilateral patients. The cumulative log survival until diagnosis for bilateral and unilateral patients followed linear and quadratic curves respectively, and supported the two-hit hypothesis for retinoblastoma. The germ cell mutation rate for retinoblastoma, assuming a single major gene, was calculated to be in the order of 9.3 X 10(-6) to 10.9 X 10(-6) for the New Zealand population.


Lung biopsy: methods, value, complications, timing, and indications.
Six methods of lung biopsy are discussed on the basis of literature reports: 1. Aspiration biopsy by fine needle, 2. split needle biopsy (Vim-Silverman), 3. cutting needle biopsy (Travenol), 4. trephine biopsy by rotating needle, 5. transbronchial biopsy, 6. open biopsy. Because of the high risk, biopsies with thick needles (methods 2--4) should be abandoned. Transbronchial biopsy is renounced because reliable results are only achieved in sarcoidosis which can be clearly diagnosed in high percentage of cases by other less dangerous procedures. In solitary tumors which could not be diagnosed by any other means aspiration biopsy is indicated because of its low risk and its diagnostic accuracy of more than 80%. In disseminated pulmonary disorders which cannot be diagnosed by any other means open lung biopsy is the most reliable method. The lung specimens can be taken under eye control. They should contain tissue from the transitional zone between diseased and unchanged areas, however. The specimens are usually big enough for additional electron and fluorescence microscopic examinations as well as dust analyses. The pathologist must be aware of all clinical data including X-ray pictures, laboratory findings, case history, and history of occupational and nonoccupational dust exposure. If these conditions are fulfilled and adequate methods are applied, lung biopsy provides diagnosis and prognosis, makes causal therapy possible, and amplifies the medical knowledge of pulmonary diseases.


Stress distribution and deformation in six tie wings Orthodontic bracket during simulated tipping - A finite element analysis.
Four tie wings brackets are widely used in orthodontics, while the Six Tie Wings Brackets (STWB) are recently emerging in fixed orthodontic appliances due to their claim for less friction and thus faster teeth movement. The aim of this work was to evaluate the stress distribution and deformation during simulated mesio-distal tipping forces in Stainless Steel (SS) six tie wings orthodontic bracket using Finite Element Analysis (FEA). A six tie wings bracket (Synergy®, RMO, USA) dimensions were measured using the Vision system and a 3D model of the bracket was constructed. A Finite Element (FE) model was developed and mesio-distal tipping forces of 1.22 N to 1.96 N (125 to 200 gm) in increments were applied on the gingival and incisal slot walls. The stress distribution and deformation were recorded at specific points in the bracket and analyzed. The maximum deformation and stress distribution for the mesial and distal tipping forces of 1.96 N were recorded as 0.137 µm and 10.60 MPa respectively. The stress concentration was more at the junction of the slot wall and the slot base. For mesial tipping,the deformation was more on the disto-incisal and mesio-gingival tie wings. Similarly, for distal tipping the deformation was more on the mesio-incisal and disto-gingival tie wings. The mid-tie wings showed minimal deformation during both distal and mesial tipping. Our study visualized both the mesial and distal tipping forces induced stress distribution in the bracket tie wing-slot junctions. The deformation was present maximum in the mesio-incisal and disto-incisal tie wings and minimal in the mid-tie wings. Clinicians should be aware of this behavior of STWB in making decisions to alter the tipping forces in the archwire to compensate for the tie wing deformation in refining the teeth position.


Proposed Prediction Model and Nomogram for Systemic Complications in Patients Undergoing Free Flap Head and Neck Reconstruction.
Postoperative complications in head and neck surgery are well-known, but a predictive model to guide clinicians in free flap reconstructions has not been established. This retrospective single-center observational study assessed 131 patients who underwent ablative surgery and received free flap reconstruction. Primary endpoint was the occurrence of systemic complications (PSC). Secondary endpoint was the generation of a nomogram of complications according to the CDC classification. In the ordinal regression model, postoperative administration of furosemide [1.36 (0.63-2.11), p < 0.0001], blood loss [0.001 (0.0004-0.0020), p = 0.004], postoperative nadir hemoglobin [-0.03 (-0.07-0.01), p = 0.108], smoking [0.72 (0.02-1.44), p = 0.043], and type of flap reconstruction [1.01 (0.21-1.84), p = 0.014] as predictors. A nomogram with acceptable discrimination was proposed (Somer's delta: 0.52). Application of this nomogram in clinical practice could help identify potentially modifiable risk factors and thus reduce the incidence of postoperative complications in patients undergoing microvascular reconstruction of the head and neck.


PHI stimulates ACTH release from pituitary tumor cell.
The identification of PHI (the 27-amino acid peptide (P) having an N-terminal histidine (H) and a C-terminal isoleucine amide (I] in median eminence suggested that PHI influences the secretory function of the anterior pituitary. The effects of PHI on ACTH release from clonal mouse pituitary corticotrophs were investigated. The secretory response to PHI was correlated with a prior increase in cyclic AMP accumulation. Both cyclic AMP synthesis and ACTH secretion were increased by PHI in a concentration-dependent manner. PHI was a less effective agonist of cyclic nucleotide synthesis and ACTH secretion than VIP. The secretory response to PHI was blocked by the calcium channel antagonist, nifedipine, and by dexamethasone. Somatostatin and oxotremorine blocked both PHI-stimulated cyclic AMP formation and ACTH secretion. The observation that VIP in high concentrations can elicit ACTH secretion from normal rat anterior pituitary suggested that a VIP-like substance may modulate ACTH secretion. However, the finding that PHI does not elicit ACTH release from primary cultures of dispersed anterior pituitary, coupled to its relatively lower potency compared to VIP, indicate that corticotrophs are not an important target for PHI.


The multistep process of hepatocarcinogenesis in cirrhosis with imaging correlation.
Hepatocarcinogenesis in the cirrhotic liver has recently become a subject of intense investigation. The development of hepatocellular nodules demonstrating varying degrees of cellular and architectural atypia suggests that these nodular lesions represent a pathway of carcinogenesis in cirrhosis of different etiologies. This pathway involves processes, such as capillarization and neoangiogenesis, leading to a gradual change in blood supply from portal to arterial, as a dysplastic nodule becomes hepatocellular carcinoma. These changes in intranodular blood supply create different enhancement patterns in the two phases of liver circulation after an intravenous contrast injection on multi-phase helical CT or dynamic gadolinium-enhanced MRI. This article reviews the current concepts regarding the vascular changes occurring in dysplastic nodules in the multistep process of hepatocarcinogenesis, along with the associated imaging manifestations. Some practical issues and dilemmas regarding the follow-up and biopsy of these lesions are also discussed.


Comparison of particle image velocimetry and the underlying agents dynamics in collectively moving self propelled particles.
Collective migration of cells is a fundamental behavior in biology. For the quantitative understanding of collective cell migration, live-cell imaging techniques have been used using e.g., phase contrast or fluorescence images. Particle tracking velocimetry (PTV) is a common recipe to quantify cell motility with those image data. However, the precise tracking of cells is not always feasible. Particle image velocimetry (PIV) is an alternative to PTV, corresponding to Eulerian picture of fluid dynamics, which derives the average velocity vector of an aggregate of cells. However, the accuracy of PIV in capturing the underlying cell motility and what values of the parameters should be chosen is not necessarily well characterized, especially for cells that do not adhere to a viscous flow. Here, we investigate the accuracy of PIV by generating images of simulated cells by the Vicsek model using trajectory data of agents at different noise levels. It was found, using an alignment score, that the direction of the PIV vectors coincides with the direction of nearby agents with appropriate choices of PIV parameters. PIV is found to accurately measure the underlying motion of individual agents for a wide range of noise level, and its condition is addressed.


Natural isoflavone biochanin A as a template for the design of new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium.
Mycobacterium avium is a difficult-to-treat pathogen able to quickly develop drug resistance. Like for other microbial species, overexpression of efflux pumps is one of the main mechanisms in developing multidrug resistance. Although the use of efflux pumps inhibitors (EPIs) represents a promising strategy to reverse resistance, to date few M. avium EPIs are known. Recently, we showed that in-house 2-phenylquinoline S. aureus NorA EPIs exhibited also a good activity against M. avium efflux pumps. Herein, we report a series of 3-phenylquinolones designed by modifying the isoflavone biochanin A, a natural EPI of the related M. smegmatis, taking into account some important SAR information obtained around the 2-phenylquinoline NorA EPIs. The 3-phenylquinolones inhibited M. avium efflux pumps with derivatives 1e and 1g that displayed the highest synergistic activity against all the strains considered in the study, bringing down (from 4- to 128-fold reduction) the MIC values of macrolides and fluoroquinolones.


Aquaporins.
Aquaporins (AQP) are members of the major intrinsic protein superfamily of integral membrane proteins, which function as specialized water channels to facilitate the passage of water through the cell membrane in animals, plants and bacterias. Ten AQP homologues named from 0 to 9 have been clones so far in mammals. They are widely distributed and more than one AQP could be present in the same cell. Most of the AQPs are only permeable to water and impermeable to small organic and inorganic molecules, except for AQP 3, 7 and 9 which are also permeable to urea and glycerol. From the hydrophobicity profile all AQPs seem to have six transmembrane domains with five connecting loops and with the amino and carboxyl termini in the cytoplasm. They are synthesized as monomers, but there is evidence suggesting that AQPs are formed in the membrane as tetrameric units, each of which has four water pores. The primary amino acid sequence contains putative phosphorylation sites for protein kinasses A and/or C or casein kinase II, and the expression and membrane protein abundance of some AQPs are known to be under hormonal regulation. The human genes for several AQPs have been cloned and an increasing number of disturbances associated to abnormal functioning of these proteins had been identified.


A prolyl oligopeptidase inhibitor, KYP-2047, reduces α-synuclein protein levels and aggregates in cellular and animal models of Parkinson's disease.
The aggregation of α-synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of α-synuclein in vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP-2047, on α-synuclein aggregation in cell lines overexpressing wild-type or A30P/A53T mutant human α-syn and in the brains of two A30P α-synuclein transgenic mouse strains. Cells were exposed to oxidative stress and then incubated with the PREP inhibitor during or after the stress. Wild-type or transgenic mice were treated for 5 days with KYP-2047 (2 × 3 mg·kg(-1) a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble α-synuclein protein levels were measured by Western blot. α-synuclein mRNA levels were quantified by PCR. The colocalization of PREP and α-synuclein,and the effect of KYP-2047 on cell viability were also investigated. In cell lines, oxidative stress induced a robust aggregation of α-synuclein,and low concentrations of KYP-2047 significantly reduced the number of cells with α-synuclein inclusions while abolishing the colocalization of α-synuclein and PREP. KYP-2047 significantly reduced the amount of aggregated α-synuclein,and it had beneficial effects on cell viability. In the transgenic mice, a 5-day treatment with the PREP inhibitor reduced the amount of α-synuclein immunoreactivity and soluble α-synuclein protein in the brain. The results suggest that the PREP may play a role in brain accumulation and aggregation of α-synuclein, while KYP-2047 seems to effectively prevent these processes.


Catalogue of 45 reference Raman spectra of minerals concerning research in art history or archaeology, especially on corroded metals and coloured glass.
Small catalogues of reference Raman spectra of interest for analysing geomaterials or biomaterials of relevance to art history or archaeology are gradually being published by different research groups. However, except for some older catalogues, they are all concerned primarily with pigments, whether inorganic or organic. Here we present for the first time a catalogue of Raman spectra of minerals that may be found in corroded metal artworks or artefacts. At the same time we include some inorganic pigments that may be found in or on stained glass. Most of the minerals analysed came from the Gallery of Mineralogy at the Muséum National d'Histoire Naturelle and most were verified by X-ray diffraction in order to augment the confidence in the mineral identity (which is not the case with many other catalogues). A number of problems encountered with mineral terminology are discussed. Comments are made on the spectra where appropriate.


A systematic review of multidisciplinary teams to reduce major amputations for patients with diabetic foot ulcers.
Multiple single-center studies have reported significant reductions in major amputations among patients with diabetic foot ulcers after initiation of multidisciplinary teams. The purpose of this study was to assess the association between multidisciplinary teams (ie, two or more types of clinicians working together) and the risk of major amputation and to compile descriptions of these diverse teams. We searched PubMed, Scopus, Cumulative Index to Nursing and Allied Health, and Cochrane Central Register of Controlled Trials from inception through May 24, 2019 for studies reporting the association between multidisciplinary teams and major amputation rates for patients with diabetic foot ulcers. We included original studies if ≥50% of the patients seen by the multidisciplinary team had diabetes, they included a control group, and they reported the effect of a multidisciplinary team on major amputation rates. Studies were excluded if they were non-English language, abstracts only, or unpublished. We used the five-domain Systems Engineering Initiative for Patient Safety Model to describe team composition and function and summarized changes in major amputation rates associated with multidisciplinary team care. A meta-analysis was not performed because of heterogeneity across studies, their observational designs, and the potential for uncontrolled confounding (PROSPERO No. 2017: CRD42017067915). We included 33 studies, none of which were randomized trials. Multidisciplinary team composition and functions were highly diverse. However, four elements were common across teams: teams were composed of medical and surgical disciplines; larger teams benefitted from having a "captain" and a nuclear and ancillary team member structure; clear referral pathways and care algorithms supported timely, comprehensive care; and multidisciplinary teams addressed four key tasks: glycemic control, local wound management, vascular disease, and infection. Ninety-four percent (31/33) of studies reported a reduction in major amputations after institution of a multidisciplinary team. Multidisciplinary team composition was variable but reduced major amputations in 94% of studies. Teams consistently addressed glycemic control, local wound management, vascular disease, and infection in a timely and coordinated manner to reduce major amputation for patients with diabetic foot ulcerations. Care algorithms and referral pathways were key tools to their success.


The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment.
Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies.


The organization of conceptual knowledge: the evidence from category-specific semantic deficits.
Questions about the organization of conceptual knowledge in the human brain can be addressed by studying patients with category-specific semantic deficits: disproportionate and even selective impairment of conceptual knowledge of one category of objects compared with other categories. Recently, consensus has emerged regarding the basic facts of category-specific semantic deficits: (1) the categories that can be disproportionately impaired or spared are 'animals', 'fruit/vegetables', and 'artifacts'; and (2) category-specific semantic deficits are not associated with disproportionate deficits for a type or modality of knowledge. Together with findings in functional neuroimaging, these data indicate a complex organization of conceptual knowledge characterized by several independent dimensions of organization.


Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats.
Benzodiazepines (BZD) are widely used for the treatment of anxiety. They enhance GABA-ergic neurotransmission through the binding on specific BDZ recognition sites, within the GABA(A) receptor-ion channel complex. However, recent studies showed that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18 kDa (TSPO). Evidence for a direct immunomodulatory action for BZD emerged from studies that demonstrated the presence of TSPO on immune/inflammatory cells. The present study was designed to analyze the effects of diazepam on rat lymphocyte parameters, specifically on phenotype, cell proliferation and cell death. The effects of both acute and long-term (21 days) diazepam (1 and 10 mg/kg/day) administrations were evaluated. Results showed that diazepam (1 mg/kg) treatment did not change the immune parameters analyzed. However, both diazepam (10 mg/kg) acute and long-term treatments decreased the number of apoptotic cells; they also increased the percentage of T cytotoxic cells; decreased the percentage of B cells and increased the corticosterone serum levels. The induction of functional tolerance was suggested for the highest dose of diazepam (10 mg/kg), but not for the smaller dose (1 mg/kg) used, at least for diazepam effects on corticosterone serum levels. Diazepam effects were discussed as being related to the number of TSPO sites present on immune cells and/or to the increased levels of serum corticosterone observed after the treatments used.


Pharmacokinetics of coumarin and its 7-hydroxy-metabolites upon intravenous and peroral administration of coumarin in man.
The pharmacokinetics of coumarin (C) upon i.v. and p.o. administration and its metabolites 7-hydroxy-coumarin (7-HC) and 7-hydroxy-coumarin glucuronide (7-HCG) have been studied. Six healthy volunteers were involved in this investigation. Four of the volunteers participated in a crossover study. Coumarin was administered i.v. and p.o. in dose sizes of 0.25 mg/kg and 0.857 mg/kg, respectively. Coumarin is rapidly absorbed p.o., however the availability to systemic circulation is less than 4%. The rest of the dose appears quantitatively as 7-HC and 7-HCG in systemic circulation suggesting an extensive firstpass effect. Coumarin and 7-HCG are best fitted to an open two-compartment model, whereas 7-HC is best fitted to an open one-compartment model. The biological half-life of both C (0.80 vs. 1.02 h) and 7-HCG (1.47 vs. 1.15 h) was not significantly different for the two routes of administration. The large total clearance of C again suggests a first-pass effect; while that of 7-HCG, which is nearly exclusively eliminated into urine, indicates active tubular secretion of the glucuronide.


Luminescence quantum yields of sound and carious dental enamel.
The absorption and emission spectra of slabs of human and bovine dental enamel were determined. The absorption and scattering coefficients and emission quantum yields were computed according to theoretical models. The samples were gradually demineralized. The absorption, scattering, and emission parameters were determined as a function of the demineralization time. Using the theoretical models combined with the experimental values, ratio of the visible and UV luminescence, and the decrease of visible emission intensity upon demineralization are explained.


Effects of surfactants on the adsorptive removal of basic dyes from water using an organomineral sorbent-iron humate.
The sorption of basic dyes (methylene blue, malachite green, rhodamine B, crystal violet) onto a nonconventional organomineral sorbent-iron humate-was examined in the presence of various kinds of surfactants. It was found that nonionic (Triton X-100) and cationic (cetyltrimethylammonium bromide) surfactants exhibited a relatively small effect on the dye sorption. Anionic surfactants (sodium dodecyl sulfate), on the other hand, affected (in most cases) dramatically the sorption of basic (cationic) dyes. Typically, the dye sorption was enhanced in the presence of low concentrations of anionic surfactants. At high surfactant concentrations, a steep decrease in the dye sorption was observed in some systems, probably due to the formation of micelles that solubilize the dye molecules and prevent their sorption. A model describing these experimental dependencies was proposed. The sorption of basic dyes onto iron humate may be described by the pseudo-second-order kinetic equation. Diffusion processes were identified as the main mechanisms controlling the rate of the dye sorption.


The bedside determination of extravascular lung water: a non-invasive double indicator technique using 123I-antipyrine, 113mIn-transferrin and external counting.
Using the formulae of Fazio and coworkers, we calculated the extravascular lung water per unit of blood volume (ELW/V) and per unit of blood flow (ELW/F) after intravenous injection of 113In-transferrin as the blood label, and 123I-antipyrine as the diffusible, i.e. water label. Time-activity curves were recorded over the right anterior upper chest wall using a mobile detector. The curves were digitalized and fitted to a gamma-variate using a GAMMA-11 computer. Area over height calculations gave the mean transit times (t). Sixteen control subjects, without evidence of cardiac or pulmonary disease, and 10 patients, with clinical and radiological evidence of left heart failure, were examined. In the control group ELW/V was 0.37 plus or minus 0.17 and ELW/F 3.39 plus or minus 1.56 (mean plus or minus 1 SD). In the patients ELW/V was 0.71 plus or minus 0.26 and ELW/F 13.10 plus or minus 5.67. The difference between both ELW/V and ELW/F for the control group and the patient group is statistically significant. Our values for ELW/V both in patients and control subjects are very similar to those obtained by Fazio and coworkers using H2 15O. However, our values for ELW/F differed from those of Fazio; this could be partly due to dependence of this parameter on the cardiac output.


Atopic dermatitis complicated by eczema herpeticum is associated with HLA B7 and reduced interferon-γ-producing CD8+ T cells.
The increased susceptibility of patients with atopic dermatitis (AD) to disseminated viral skin infections such as eczema herpeticum (ADEH+) is poorly understood. The primary goal of the current study was to determine whether ADEH+ subjects have identifiable defects in cell-mediated immunity that reduce their ability to control viral infections. In this study, we evaluated cytokine expression by various subsets of peripheral blood mononuclear cells from ADEH+ (n = 24) compared with AD without a history of viral infections (ADEH-) (n = 20) before and after treatment with herpes simplex virus (HSV). We found that interferon (IFN)-γ expression after HSV treatment was lower in the CD8+ T cells and monocytes from patients with ADEH+ compared with patients who are ADEH- or nonatopic. Given the induction of CD8+ T cells as the result of antigen presentation by human leucocyte antigen (HLA) class I, consistent with the findings described above we also found that the HLA B7 allele was significantly associated with risk of the ADEH+ phenotype (odds ratio = 1·91, P = 0·02, 125 ADEH+ and 161 ADEH- subjects). These data suggest that defects in viral-induced IFN-γ from CD8+ T cells contribute to the ADEH+ phenotype.


The efficacy, safety, and adverse events of azapirones in anxiety disorders: A systematic review and meta-analysis of randomized controlled trials.
Azapirones have been proposed as anxiety and mood modulators. We assessed azapirones' viability in anxiety disorders via systematic review and random-effects meta-analysis, inquiring PubMed/MEDLINE/CENTRAL/WHO-ICTRP/WebOfScience/VIP up-to 05/01/2023. We conducted sensitivity, and subgroup analyses assessing heterogeneity, publication bias, risk of bias, and confidence in the evidence within the GRADE framework. Symptom reduction (mean difference/MD), study-defined response (risk ratios/RRs), and acceptability were co-primary outcomes. Adverse events and withdrawal were secondary. Seventy studies were included. In generalized anxiety disorder (GAD), azapirones largely outperformed placebo (MD=-4.91, 95%C.I.[-5.91, -3.90], Hedges'g -1.37 [-1.02, -0.73]), k = 22, n = 2,567; RR=1.64, 95%C.I.[1.45, 1.86], k = 9, n = 1,346). While azapirones overlapped benzodiazepines in symptom reduction (MD=-0.12, 95%C.I.[-0.70, 0.45], k = 34, n = 3,160), they were slightly outperformed in response rate (RR=0.94, 95%C.I.[0.90, 0.99], k = 18, n = 2,423). Azapirones overlapped SRIs (MD=0.09, 95%C.I.[-0.49, 0.67], k = 8, n = 747; RR=0.97, 95%C.I.[0.89, 1.07], k = 7, n = 737). Confidence in estimates was high/moderate vs. placebo, moderate/low vs. benzodiazepine, very-low vs. SRIs. Azapirones failed to outperform the placebo in panic and social anxiety disorders. Azapirones overlapped placebo and SRIs in drop-out rates, while they showed higher treatment discontinuation rates than benzodiazepines (RR=1.33, 95%C.I.[1.16, 1.53], k = 23, n = 2,768). Azapirones caused less sedation/fatigue/drowsiness/weakness/cognitive issues than benzodiazepines, resembling placebo. They caused more nausea and dizziness than placebo, more headache and nausea than benzodiazepines, and less nausea and xerostomia than SRIs. Azapirones proved effective and relatively well-tolerated for GAD. They should be preferred over benzodiazepines, especially in the long-term, considering their lower sedation and addiction potential, representing a potential SRI alternative. Further research is warranted to prove efficacy in panic and social anxiety.


A gut feeling of the PXR, PPAR and NF-kappaB connection.
Bowel diseases reveal the complex interplay of sensing and signalling pathways in maintaining healthy homeostasis of the intestine. Recent studies of the xenobiotic nuclear receptor, pregnane X receptor and the inflammatory mediator nuclear transcription factor kappaB (NF-kappaB) reveal a functional link between xenobiotic neutralization and inflammation and explain how certain xenobiotics can affect the immune response. Furthermore, another nuclear receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma) has been shown to produce beneficial effects in experimental inflammatory bowel diseases by repression of NF-kappaB thereby reducing inflammation, whilst its close relative PPAR beta/delta appears at a central position in signalling pathways involved in the progression of colon cancer. Recently accumulated knowledge on the action of these nuclear receptors and NF-kappaB in intestinal homeostasis may provide the rationale for the development of innovative treatment strategies with selective receptor modulators.


Conditioning, awareness, and the hippocampus.
For the past 50 years, psychologists have wrestled with questions regarding the relationship between conscious awareness and human conditioned behavior. A recent proposal that the hippocampus mediates awareness during trace conditioning (Clark, Squire, Science 1998;280:77-81) has extended the awareness-conditioning debate to the neuroscience arena. In the following commentary, we raise specific theoretical and methodological issues regarding the Clark and Squire study and place their finding into a broader context. Throughout our discussion, we consider the difficulties in assessing subjective awareness, the importance of establishing necessary and sufficient conditions for cognitive mediation effects, the influence of conditioned response modality, and the nature of hippocampal requirements across conditioning protocols. It is clear that trace eyeblink conditioning is a hippocampal-dependent task, but whether awareness is a necessary component of trace conditioning is not definitively proven. We propose that future functional neuroimaging studies and behavioral experiments using on-line measures of awareness may help clarify the relationship among classical conditioning, awareness, and the hippocampus.


Tregs defects caused delayed hypersensitivity reactions to multiple disinfectants following with debridement: A case report and literature review.
Following debridement, the skin and mucous membranes around the wound must be disinfected with broad-spectrum disinfectants like Iodophor, 75 % ethanol, chlorhexidine, and bromogeramine. Despite the fact that it is rarely reported, skin allergy to disinfectants is extremely detrimental to wound recovery after debridement. In this study, a 29-year-old man with no previous allergic history developed delayed contact dermatitis after being exposed to multiple disinfectants, including iodophor, 75 % ethanol, and Erythromycin ointment. Given the possibility of the patient's allergic constitution, skin patch tests were repeated to confirm the allergic disinfectants. To avoid the allergy, the wound was simply rinsed with 0.9 % sodium chloride solution and Cefdinir (0.1 g, tid) was taken orally, while all local disinfectants were discontinued. The wound healing process was gradually accelerated, and allergic symptoms were alleviated. Furthermore, our findings revealed that the frequency and immunosuppressive function of Tregs were significantly lower in patients than in healthy controls (P < 0.05). By minimizing allergic reactions and providing appropriate wound care, the use of 0.9 % sodium chloride solution with oral antibiotics could expedite the healing process. This enabled the wound to close faster and reduces the risk of complications. The use of 0.9 % sodium chloride solution for wound irrigation, combined with oral administration of antibiotics, could be modified to mitigate further allergic reactions and enhance the recovery process following debridement. However, individual patient characteristics and medical history should also be taken into consideration when making these alterations.


The DRD2 Taq1A A1 Allele May Magnify the Risk of Alzheimer's in Aging African-Americans.
Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys cognitive skills and the ability to perform the simplest tasks. More than 5 million Americans are afflicted with Alzheimer's; a disorder which ranks third, just behind heart disease and cancer, as a cause of death for older people. With no real cure and in spite of enormous efforts worldwide, the disease remains a mystery in terms of treatment. Importantly, African-Americans are two times as likely as Whites to develop late-onset Alzheimer's disease and less likely to receive timely diagnosis and treatment. Dopamine function is linked to normal cognition and memory and carriers of the DRD2 Taq1A A1 allele have significant loss of D2 receptor density in the brain. Recent research has shown that A1 carriers have worse memory performance during long-term memory (LTM) updating, compared to non-carriers or A2-carriers. A1carriers also show less blood oxygen level-dependent (BOLD) activation in the left caudate nucleus which is important for LTM updating. This latter effect was only seen in older adults, suggesting magnification of genetic effects on brain functioning in the elderly. Moreover, the frequency of the A1 allele is 0.40 in African-Americans, with an approximate prevalence of the DRD2 A1 allele in 50% of an African-American subset of individuals. This is higher than what is found in a non-screened American population (≤ 28%) for reward deficiency syndrome (RDS) behaviors. Based on DRD2 known genetic polymorphisms, we hypothesize that the DRD2 Taq1A A1 allele magnifies the risk of Alzheimer's in aging African-Americans. Research linking this high risk for Alzheimer's in the African-American population, with DRD2/ANKK1-TaqIA polymorphism and neurocognitive deficits related to LTM, could pave the way for novel, targeted pro-dopamine homeostatic treatment.


Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors.
Diabetes mellitus is a worldwide epidemic affecting the health of millions of people. While type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas, type 2 diabetes (T2D) results from a combination of insulin resistance and beta cell insulin secretory defect. Clear definition and diagnosis of these two types of diabetes has been increasing more and more difficult, leading to the inclusion of a new category, namely double or hybrid diabetes (DD) that demonstrates symptoms of both T1D and T2D via the accelerator hypothesis. In this review, we discuss the worldwide prevalence of DD, its main physiological characteristics, including beta-cell autoimmunity, insulin resistance, and cardiovascular disease, the main risk factors of developing DD, mainly genetics, obesity and lifestyle choices, as well as potential treatments, such as insulin titration, metformin and behavioural modifications. Increasing awareness of DD among the general population and primary care practitioners is necessary for successfully treating this complex, hybrid disease in the future.


Sorption of (226)Ra from oil effluents onto synthetic cation exchangers.
Increasing environmental awareness is being urged for the safe disposal of (226)Ra-contaminated production water generated in the oil industry. Birnessite, antimony silicate and their cationic derivatives were studied for the take-up of (226)Ra using the batch-type method under experimentally determined parameters, viz. contact time, solution-solid ratio and (226)Ra concentration. Data was expressed in terms of distribution coefficients. Sorption experiments were performed in different concentrations of nitric acid in order to speculate the mechanism of (226)Ra uptake. Variation in the magnitude of sorption efficiency of the materials in the presence of the major components of waste streams, i.e. Na(+), K(+) and Ca(2+), revealed that K(+) was the greatest competitor and Na(+) the least. The application of the materials to sorb (226)Ra from actual oil co-production water samples, collected from Der Ezzor and Al Fourat petroleum companies (DEZPC and AFPC), was interpreted in terms of the exchange properties of the materials and water characterisation. Of the parameters studied, the selectivity of materials was shown to be greatly dependent on the pH of wastewater to be treated.


King's Parkinson's Disease Pain Questionnaire: reliability and convergent construct validity.
to assess the evidence of reliability and convergent construct validity of the King's Parkinson's Disease Pain Questionnaire. psychometric study of 75 older adults with Parkinson's disease. The instrument was applied by two researchers separately and reapplied by one researcher 15 days later. In terms of reliability, internal consistency was assessed using the Cronbach's alpha test and stability using the intraclass correlation coefficient. Scores of the King's Parkinson's Disease Pain Questionnaire were compared to those of the Geriatric Pain Measure in the assessment of construct validity. the mean Cronbach's alpha obtained between the three assessments was above 0.60, the intraclass correlation between the three assessments was above 0.90, and there was a weak but significant correlation between the two applied scales. the instrument showed adequate evidence of convergent construct validity and reliability, and can be used in clinical practice.