Successful ovarian stimulation and pregnancy in an infertile woman with Rathke's cleft cyst: a case report.
To report a case of successful ovarian stimulation and pregnancy in an infertile woman with Rathke's cleft cyst (RCC). This is a case report of a 32-year-old infertile woman with RCC presenting with secondary amenorrhea and hypogonadotropic hypogonadism (HH). Three rounds of ovarian stimulation and ovulation induction by means of HMG and HCG were performed (two before HSG and one after HSG). HSG was performed after two rounds of ovulation induction without pregnancy to assess the fallopian tubes and uterine cavity of the patient. Serum beta-human chorionic gonadotropin (β-HCG) and ultrasound examination were performed after the third round of ovulation induction to confirm successful pregnancy. HSG revealed that the uterine cavity was normal and that the bilateral fallopian tubes were unobstructed. Four weeks after the third round of ovulation induction, the β-HCG test was positive (10261 μg/L), and ultrasound examination showed an intrauterine early gestational sac with an embryo (10*7 mm) and a primitive heart tube pulse. Infertility accompanied by RCC is rare in the clinic. Clarifying the cause of infertility and secondary amenorrhea is very important for achieving a successful pregnancy. This case demonstrates that such infertility can be treated effectively with ovarian stimulation and ovulation induction using HMG and HCG. To the best of our knowledge, this is the first case report of infertility accompanied by RCC.


Vocal acoustic biomarkers of depression severity and treatment response.
Valid, reliable biomarkers of depression severity and treatment response would provide new targets for clinical research. Noticeable differences in speech production between depressed and nondepressed patients have been suggested as a potential biomarker. One hundred five adults with major depression were recruited into a 4-week, randomized, double-blind, placebo-controlled research methodology study. An exploratory objective of the study was to evaluate the generalizability and repeatability of prior study results indicating vocal acoustic properties in speech may serve as biomarkers for depression severity and response to treatment. Speech samples, collected at baseline and study end point using an automated telephone system, were analyzed as a function of clinician-rated and patient-reported measures of depression severity and treatment response. Regression models of speech pattern changes associated with clinical outcomes in a prior study were found to be reliable and significant predictors of outcome in the current study, despite differences in the methodological design and implementation of the two studies. Results of the current study replicate and support findings from the prior study. Clinical changes in depressive symptoms among patients responding to the treatments provided also reflected significant differences in speech production patterns. Depressed patients who did not improve clinically showed smaller vocal acoustic changes and/or changes that were directionally opposite to treatment responders. This study supports the feasibility and validity of obtaining clinically important, biologically based vocal acoustic measures of depression severity and treatment response using an automated telephone system.


Association of androgen with gender difference in serum adipocyte fatty acid binding protein levels.
Clinical investigations have indicated women have higher levels of adipocyte fatty acid binding protein (A-FABP) than men. The present study aimed to identify factors related to gender difference in serum A-FABP levels. A total of 507 participants (194 men, 132 premenopausal women, and 181 postmenopausal women) were enrolled in the present study. Serum A-FABP levels increased in the order from men to premenopausal women to postmenopausal women in both body mass index categories (<25.0 and ≥25.0 kg/m(2); all P < 0.05). Multiple stepwise regression analyses showed that after adjustment for factors related to serum A-FABP levels, the trunk fat mass was an independent and positive factor of serum A-FABP levels. For men, total testosterone was associated independently and inversely with serum A-FABP levels. For pre- and postmenopausal women, bioavailable testosterone and total testosterone were independent and positive factors associated with serum A-FABP levels, respectively. The present study demonstrated that the androgen was correlated with the serum A-FABP levels negatively in men, but positively in women. With these effects on the fat content, especially trunk fat, androgen might contribute to the gender difference in serum A-FABP levels.


Perinatal protein restriction reduces the inhibitory action of serotonin on food intake.
Early malnutrition has been associated with a high risk of developing obesity, diabetes and cardiovascular diseases in adulthood. In animals, poor perinatal nutrition produces hyperphagia and persistent increased levels of serotonin (5-HT) in the brain. Inasmuch as 5-HT is directly related to the negative regulation of food intake, here we have investigated whether the anorexic effects of 5-HT are altered by protein malnutrition. Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 35 days their feeding behaviour was evaluated after the administration of DL-fenfluramine (DL-FEN), an anorexic compound that blocks the reuptake of 5-HT and stimulates its release. Male offspring born to protein-restricted dams exhibited significantly decreased body weight and hyperphagia compared with controls. DL-FEN dose-dependently reduced the 1 h chow intake at the onset of the dark cycle in both control and undernourished rats. However, the hypophagic effects of DL-FEN were significantly attenuated in animals submitted perinatally to protein restriction. The stimulatory action of DL-FEN on c-fos immunoreactivity within the paraventricular nucleus of the hypothalamus was also decreased in low-protein-fed rats. Further pharmacological analysis with selective 5-HT(1B) and 5-HT(2C) receptor agonist showed that the reduced anorexic effects of 5-HT in malnourished animals were coupled to a desensitization of 5-HT(1B) receptors. These observations indicate that the hyperphagia associated with metabolic programming is at least partially related to a reduced regulatory function of 5-HT on food intake.


An electrophysiological analysis of the effects of amine-uptake blockers and alpha-adrenoceptor blockers on adrenergic neuromuscular transmission.
1 An electrophysiological study has been made of the effects of either blocking noradrenaline (NA) uptake or alpha-adrenoceptors on conduction in adrenergic preterminal axons and on NA release. 2 The excitatory junction potential (e.j.p.) evoked by a single stimulus increased slightly in duration (maximum 20%) in the presence of high concentrations of desipramine or cocaine (larger than or equal to 1 mug/ml) but there was no change in the spontaneous miniature excitatory junction potential (m.e.j.p.s); the single compound preterminal action potential was decreased in amplitude by a maximum of 10%. The e.j.p., m.e.j.p. and the terminal action potential were not altered by lower concentrations of these drugs (less than mug/ml). 3 The increased decline of the e.j.p. amplitude observed during the first few hundred impulses at high frequencies (10 Hz) in the presence of desipramine or cocaine was accompanied by a similar decline in the amplitude of the preterminal compound action potential, suggesting that the latter gave rise to the former. 4 These observations suggest that the action on post-synaptic alpha-adrenoceptors of NA released by single impulses is terminated by diffusion, and that any NA which is subsequently taken up into nerves is metabolized. 5 All the alpha-adrenoceptor blocking drugs tested reversed the normal depression in e.j.p. amplitude observed during the first few hundred impulses at high frequencies to facilitation; this was unaccompanied by any changes in the preterminal compound action potential. 6 Alpha-Adrenoceptor blocking drugs did not alter the potentiating effect which a conditioning impulse had on the amplitude of the e.j.p. evoked by a subsequent test impulse. The facilitated release of NA during trains of impulses was quantitatively predicted in terms of the addition of the individual potentiations introduced by each impulse in the train. 7 It is suggested that if there is an auto-inhibition of NA release, then it is unlikely that the pre- and post-synaptic alpha-adrenoceptors are identical.


Folkscience: coarse interpretations of a complex reality.
The rise of appeals to intuitive theories in many areas of cognitive science must cope with a powerful fact. People understand the workings of the world around them in far less detail than they think. This illusion of knowledge depth has been uncovered in a series of recent studies and is caused by several distinctive properties of explanatory understanding not found in other forms of knowledge. Other experimental work has shown that people do have skeletal frameworks of expectations that constrain richer ad hoc theory construction on the fly. These frameworks are supplemented by an ability to evaluate and rely on the division of cognitive labour in one's culture, an ability shown to be present even in young children.


Primary structures of alpha-crystallin A chains of elephant, whale, hyrax and rhinoceros.
As part of a study of the evolutionary development of the eye lens protein alpha-crystallin the 173-residue A chain of this protein has been studied in elephant, whale, hyrax and rhinoceros. The primary structures were inferred mainly from amino acid compositions of peptides obtained by enzymic digestions and CNBr cleavage. The positions of substitutions, as compared to the known bovine A chain, were confirmed by Edman degradation. In accordance with the previously observed slow rate of evolution of the A chain only a small number of substitutions was found among these species. Elephant and hyrax share a number of unique substitutions, strongly indicating a common ancestry of these two species within the mammalian class.


Alterations in uptake and metabolism of aspartate and glutamate in brain of thiamine deficient animals.
The high affinity uptake systems of aspartate, glutamate, glycine and taurine were studied in synaptosomal preparations isolated from the cerebellum, medulla-pons and the telencephalon of rats made thiamine deficient (TD) by diet or pyrithiamine (PT). There was a significant enhancement in the uptake of asparate/glutamate (probably transported by the same carrier) by the synaptosomal preparations of the cerebellum only, in both groups of thiamine-deficient animals as compared to controls. This was due to an increase in the number of uptake sites and not to an alteration of the binding affinity. Aspartate levels decreased significantly in all three brain areas of PT-treated animals and this change was greatest in the medulla-pons and the cerebellum and least in the cortex. Glutamate and serine levels were significantly decreased only in the medulla-pons whilst the concentration of glutamine was significantly increased in the three brain regions studied. The changes in both uptake and levels of amino acids in TD rats were reversed by thiamine therapy. Though the uptake studies do not discriminate between an altered aspartergic or glutamergic system, the changes in the levels of aspartate in the cerebellum suggest that the aspartergic system is involved. Since earlier studies showed a selective impairment in the high affinity uptake of serotonin by cerebellar synaptosomes, thiamine deficiency could impair cerebellar function by inducing an imbalance in its neurotransmitter systems.


A scanning electron microscopic study of external root resorption in replanted dog teeth.
Root resorption after replantation of mature permanent dog incisors was examined by scanning electron microscopy. Three groups consisting of three extracted teeth each were kept in a saline solution for 5, 30, and 120 min before replantation. The first group was replanted with the pulp intact. The second and third groups were replanted after root canal filling by Calciobiotic Root Canal Sealer. After 90 days, the teeth were extracted and the apical root surfaces were examined. Severe inflammatory root resorption was observed in the first (intact pulp) group. For the root canal filled teeth, the degree of root resorption was observed to be much less in those kept in saline for 30 min than in those kept for 120 min.


Metalloporphyrin-Based Metal-Organic Frameworks on Flexible Carbon Paper for Electrocatalytic Nitrite Oxidation.
Deposition of redox-active metal-organic frameworks (MOFs) as thin films on conductive substrates is of great importance to improve their electrochemical performance and durability. In this work, a series of metalloporphyrinic MOF crystals was successfully deposited as thin films on carbon fiber paper (CFP) substrates, which is an alternative to rigid glass substrates. The specific dimensions of the obtained films could be adjusted easily by simple cutting. Metalloporphyrinic MOFs on CFP with different active metal species have been employed for electrochemical conversion of the carcinogenic nitrite into the less toxic nitrate. The MOFs on CFP exhibit remarkable improvement in terms of the electrocatalytic performance and reusability compared with the electrodes prepared from MOF powder. The contribution from metal species of the porphyrin units and reaction mechanisms was elucidated based on the findings from X-ray photoelectron spectroscopy (XPS) and in situ X-ray absorption near edge structure (XANES) measured during the electrochemical reaction. By integrating the redox-active property of metalloporphyrinic MOFs and high conductivity of CFP, MOF thin films on CFP provided a significant improvement of electrocatalytic performance to detoxify the carcinogenic nitrite with good stability.


Arthroscopic-assisted latissimus dorsi transfer for subscapularis deficiency.
Few salvage procedures have been described in case of irreparable subscapularis tear and with variable outcomes. Latissimus dorsi transfer has been widely proposed as a transfer for irreparable posterio-superior rotator cuff tear with good outcomes. The anatomic feasibility of the latissimus dorsi to reconstruct the antero-superior irreparable rotator cuff tear has been suggested, but no clinical study has ever been published. We hypothesized that it was possible to use an arthroscopic-assisted latissimus dorsi transfer to reconstruct the subscapularis function. Five patients were enrolled. A 5-7-cm axillary incision was performed to release the latissimus dorsi tendon from its humeral insertion, the teres major muscle and the apex of the scapula. Afterwards, under arthroscopic control, a 7-mm-diameter tunnel was drilled at the anterior and superior part of the humeral head with an oblique inferior and posterior direction. The tubularized latissimus dorsi tendon was introduced into the tunnel and fixed with a ZipLoop on the posterior humeral cortex. The authors show overall good experience with this technique. Level IV-a, case series.


Effects of probiotic administration on zebrafish development and reproduction.
As the consumption of probiotics increases worldwide, scientists focus on identifying bacterial strains able to improve human life quality and evidence the biological pathways affected by probiotic treatment. In this review, some recent observations on the effects of changes of microbiota on zebrafish metabolism were discussed. In addition, the effects of Lactobacillus rhamnosus - a component of the human gut microflora - as a diet supplement on Danio rerio were presented. When administered chronically, L. rhamnosus may affect larval development and the physiology of reproductive system in the zebrafish model. It was hypothesized exogenous L. rhamnosus accelerates larval growth and backbone development by acting on insulin-like growth factors-I (igfI) and -II (igfII), peroxisome proliferator activated receptors-α and -β, (pparα,β) vitamin D receptor-α (vdrα) and retinoic acid receptor-γ (rarγ). Gonadal differentiation was anticipated at 6weeks together with a higher expression of gnrh3 at the larval stage when L. rhamnosus was administered throughout development. Moreover, brood stock alimented with a L. rhamnosus-supplemented diet showed better reproductive performances as per follicles development, ovulated oocytes quantification and embryos quality. A plausible involvement of factors such as leptin, and kiss1 and 2 in the improvements was concluded. The observations made on the physiology of female reproduction were correlated with the gene expression of a gigantic number of factors as the aromatase cytochrome p 19 (cyp19a), the vitellogenin (vtg) and the α isoform of the E2 receptor (erα), luteinizing hormone receptor (lhr), 20-β hydroxysteroid dehydrogenase (20β-hsd), membrane progesterone receptors α and β, cyclin B, activinβA1, smad2, transforming growth factor β1 (tgfβ1), growth differentiation factor9 (gdf9) and bone morphogenetic protein15 (bmp15.) A model in which the exogenous L. rhamnosus in the digestive tract of zebrafish from the first days of life through sexual maturation positively influences the physiological performances of zebrafish was evidenced and a number of pathways that might be influenced by the presence of this human probiotic strain were proposed.


Infant gut microbiota characteristics generally do not modify effects of lipid-based nutrient supplementation on growth or inflammation: secondary analysis of a randomized controlled trial in Malawi.
An unhealthy gut microbial community may act as a barrier to improvement in growth and health outcomes in response to nutritional interventions. The objective of this analysis was to determine whether the infant microbiota modified the effects of a randomized controlled trial of lipid-based nutrient supplements (LNS) in Malawi on growth and inflammation at 12 and 18 months, respectively. We characterized baseline microbiota composition of fecal samples at 6 months of age (n = 506, prior to infant supplementation, which extended to 18 months) using 16S rRNA gene sequencing of the V4 region. Features of the gut microbiota previously identified as being involved in fatty acid or micronutrient metabolism or in outcomes relating to growth and inflammation, especially in children, were investigated. Prior to correction for multiple hypothesis testing, the effects of LNS on growth appeared to be modified by Clostridium (p-for-interaction = 0.02), Ruminococcus (p-for-interaction = 0.007), and Firmicutes (p-for-interaction = 0.04) and effects on inflammation appeared to be modified by Faecalibacterium (p-for-interaction = 0.03) and Streptococcus (p-for-interaction = 0.004). However, after correction for multiple hypothesis testing these findings were not statistically significant, suggesting that the gut microbiota did not alter the effect of LNS on infant growth and inflammation in this cohort.


Vaccination of pigs with the S48 strain of Toxoplasma gondii--safer meat for human consumption.
As clinical toxoplasmosis is not considered a problem in pigs, the main reason to implement a control strategy against Toxoplasma gondii (T. gondii) in this species is to reduce the establishment of T. gondii tissue cysts in pork, consequently reducing the risk of the parasite entering the human food chain. Consumption of T. gondii tissue cysts from raw or undercooked meat is one of the main sources of human infection, with infected pork being considered a high risk. This study incorporates a mouse bioassay with molecular detection of T. gondii DNA to study the effectiveness of vaccination (incomplete S48 strain) in its ability to reduce tissue cyst burden in pigs, following oocyst (M4 strain) challenge. Results from the mouse bioassay show that 100% of mice which had received porcine tissues from vaccinated and challenged pigs survived compared with 51.1% of mice which received tissues from non-vaccinated and challenged pigs. The presence (or absence) of T. gondii DNA from individual mouse brains also confirmed these results. This indicates a reduction in viable T. gondii tissue cysts within tissues from pigs which have been previously vaccinated with the S48 strain. In addition, the study demonstrated that the main predilection sites for the parasite were found to be brain and highly vascular muscles (such as tongue, diaphragm, heart and masseter) of pigs, while meat cuts used as human food such as chop, loin, left tricep and left semitendinosus, had a lower burden of T. gondii tissue cysts. These promising results highlight the potential of S48 strain tachyzoites for reducing the number of T. gondii tissues cysts in pork and thus improving food safety.


Regulating Na deposition by constructing a Au sodiophilic interphase on CNT modified carbon cloth for flexible sodium metal anode.
Na metal anode has attracted increasing attentions as the anode of sodium ion batteries (SIBs) due to its high theoretical capacity, low redox potential and high abundance. However, the formation of uncontrollable Na dendrite during repeated plating/stripping cycles hinders its further development and application. Herein, a sodiophilic Na metal anode host is developed by sputtering gold nanoparticles (Au NPs) into interconnected carbon nanotube modified carbon cloth (CNT/CC) to form a Au-CNT/CC architecture. Sodiophilic Au NPs effectively guide the Na metal uniform deposition and three-dimensional (3D) microporous structure offers a large surface area for nucleation and reducing the current densities. The regulated uniform Na metal deposition mechanism is investigated by the in-situ optical microscopy and simulation analysis. As a result, Au-CNT/CC electrode exhibits a low nucleation overpotential (2.2 mV) and stable cycle performance for 1600 h at 1 mA cm-2 with 2 mAh cm-2. Moreover, it even exhibits a long cycle stability for more than 800 h at 5 mA cm-2 with 2 mAh cm-2. To explore its application, a full cell coupled with a sodium vanadium phosphate coated with carbon layer (NVP@C) cathode is assembled and delivers an average discharge capacity of 80.6 mAh g-1 and coulombic efficiency of 99.6% for 400 cycles at 100 mAh g-1. Furthermore, a flexible pouch cell with Na@Au-CNT/CC as the anode is fabricated and demonstrated good flexibility and future application of wearable electronics.


Effects of experimental hypogravity on peroxidase and cell wall constituents in the dwarf marigold.
Dwarf Marigolds grown from seed under experimental hypogravity are modified in lignin content, hemicellulose composition, and peroxidase activity. The two conditions used, clinostats and flotation, induced changes differing in magnitude but qualitatively similar. Most responses on clinostats required corrections for vertical axis rotational effects, thus limiting the value of these instruments in free-fall simulation. These findings extend earlier observations suggesting that increased peroxidase and decreased lignin are characteristic of growth under experimental hypogravity.


Mining of mortality-related findings in rare bleeding disorders: a retrospective study from two centers.
Rare bleeding disorders include inherited coagulation disorders except for von Willebrand disease and hemophilia A and B. These disorders affect both men and women worldwide and mainly have an autosomal recessive pattern of inheritance. Given the paucity of cases of rare bleeding disorders, there are limited data regarding some topics among bleeding disorders. This retrospective study from 2005-2019 collected demographic data and the causes of death among cases with rare bleeding disorders from 2 provinces of Iran. Overall, 5 deaths were reported, including 3 cases with factor V deficiency, a case with factor XIII deficiency, and a case with combined factor V and factor VIII deficiencies. The main causes of death were bleeding in the central nervous system (2 cases; 1 with factor V deficiency and 1 with combined factor XIII deficiency). Post-partum hemorrhage was the cause of death in a woman with factor V deficiency while anaphylaxis shock was the cause of death in the case with combined factor V and factor VIII deficiencies. A woman with factor V deficiency died from an internal bleeding episode. Gathering data on the causes of death in rare bleeding disorders through worldwide registries can be helpful for the management of this rare group of bleeding disorders.


New trends in cryoenzymology : II. - Aqueous solutions of enzymes in apolar solvents.
In order to set up new procedures to investigate enzyme systems at subzero temperatures in pure aqueous media, we used micromicellar solutions which are homogeneous, optically transparent and of low viscosity in that range of temperatures. The preparation and the main properties of such solutions are described along with the behavior of enzyme-substrate intermediates. A critical discussion of results permits to examine advantages as well as limitations of this very promising procedure.


Early MRI findings of the acetabulum and femoral head in a dysplastic hip resulting in a rapid destruction of the hip joint.
We documented a case of rapidly destructive arthrosis of the hip joint (RDA), in whom abnormal findings were observed not only in the femoral head but also in the acetabulum on magnetic resonance images (MRI) in the early stage. Radiographs made 1 month after the onset of pain showed a slight narrowing of the joint space. MRI obtained 2 months after the onset detected small foci of low signal intensity in the subchondral area of the femoral head on the T1-weighted images, and a linear pattern of high signal intensity in the lateral side of the acetabulum on the T2-weighted images. During the 17-month follow-up period, this case eventually underwent massive destruction of the femoral head as well as the acetabulum.


Biofilm microenvironment activated supramolecular nanoparticles for enhanced photodynamic therapy of bacterial keratitis.
Infectious keratitis caused by bacterial biofilms is one of the main causes of corneal blindness, presenting a serious threat to public health. In this study, matrix metalloproteinase (MMP)-sensitive supramolecular nanoparticles (denoted as MMP-S NPs) were constructed for enhancing photodynamic antibacterial effect against biofilm-associated bacterial keratitis. MMP-S NPs were prepared by host-guest self-assembly of chlorin e6 (Ce6) conjugated β-cyclodextrin (β-CD) prodrug (β-CD-Ce6) and MMP-9-sensitive peptides (YGRKKKRRQRRR-GPLGVRG-EEEEEE) terminated with adamantane (Ad) (Ad-MMP-S PEPs). MMP-S NPs with EEEEEE peptide shell had a negatively charged surface, preventing adhesion to the normal ocular surface or healthy corneal cells, thus enhancing tear retention time. After arriving at the infected lesions, the protective EEEEEE peptide shell of MMP-S NPs was removed, triggered by overexpressed MMP-9 in the keratitis microenvironment. The subsequently exposed cationic peptides helped the nanoparticles penetrate and accumulate in biofilms as well as bind to Gram-negative bacteria Pseudomonas aeruginosa (P. aeruginosa), which eventually improved the photodynamic antibacterial effect. Furthermore, the P. aeruginosa keratitis model verified the high effectiveness of a topical eye drop formulation of MMP-S NPs in killing bacteria by destroying the bacterial membrane as a result of in situ photodynamic activation of reactive oxygen species (ROS) formation under light irradiation. Moreover, the inflammatory response in the cornea was inhibited to a great extent. As a result, further damage to the corneal tissue was completely suppressed. This research provides a viable antibacterial alternative to fight against bacterial keratitis through effective elimination of infectious bacteria and eradication of bacterial biofilms in the cornea.


Computed tomography in meningitis.
Computed tomography in 34 cases of meningitis has revealed a spectrum of findings. In acute cases these include enlargement of the subarachnoid spaces, generalized contrast enhancement of the meninges and ependyma, sterile and pyogenic subdural collections, cortical infarction, and cerebral necrosis.


Phenotypic expression of a novel C282Y/R226G compound heterozygous state in HFE hemochromatosis: molecular dynamics and biochemical studies.
Most adults affected with hereditary hemochromatosis are homozygous for a single point mutation of HFE (p.Cys282Tyr). Apart from the compound heterozygous state for the p.Cys282Tyr mutant and the widespread p.His63Asp variant allele, other rare HFE mutations can be found in trans and may have clinical impact. In the present report we describe the structural and functional consequences of a new mutation, namely the p.Arg226Gly which was inherited in trans with the p.Cys282Tyr allele in a patient affected with a mild iron overload. Because the R226G substitution is located in the vicinity of the normal Cys225S-S282Cys disulfide bond we initially investigated the structure of the variant by molecular dynamics techniques in order to estimate the effect of the mutation on the global structure of HFE domain α3. We found that the solvation free energy, hydrophobicity and formation of salt bridges are slightly modified with the global secondary structure of the α3 domain being conserved. In a previous paper, we demonstrated that the Q283P substitution leads to the loss of the normal Cys225S-S282Cys disulfide bridge. Similar to the Q283P substitution, the R226G substitution does not substitute a residue directly involved in the formation of the disulfide bridge. However, unlike the p.Gln283Pro variant which destroyed the normal disulfide bridge, the R226G mutation does not affect the normal Cys225S-S282Cys bridge. Furthermore based on cell line studies we clearly show that the mutation does not prevent cell surface localization, β2-microglobulin association and binding to transferrin receptor 1. This new compound heterozygous phenotype is very close to those of the C282Y/H63D compound heterozygous patients who display the biochemical hemochromatosis phenotype but with lower body iron stores than C282Y homozygotes. Our results do not exclude unknown genetic and/or metabolic factors that may act synergistically to increase the ferritin level.


Microstructures, physical and sustained antioxidant properties of hydroxypropyl methylcellulose based microporous photophobic films.
Hydroxypropyl methylcellulose (HPMC)/sodium citrate (SC)/lipid tea polyphenol (LTP) photophobic films with different pore sizes from micron scale to nanometer scale were prepared by regulating the SC content (1-7%). The microstructures, physical and sustained antioxidant properties of these films were studied by using wide angel X-ray diffraction, small angle X-ray scattering (SAXS), scanning electron microscope, whiteness meter, ultraviolet spectrophotometer, texture analyzer and peroxide value test. Composite films with higher SC content showed larger pore size and whiteness. With the increasing SC content, crystallinity first increased then decreased. The addition of SC decreased the Ds (surface fractal dimension) value, smoothness of the cross-section structure, tensile strength, elongation and modulus of composite films. HPMC/SC/LTP microporous films possessed control-release property in oil system, reflected by the lowest peroxide value of peanut oil enclosed in film with 3% SC during three weeks, meaning this film showed the best sustained antioxidant property.


Comparison of muscle and skin perfusion over the ischial tuberosities in response to wheelchair tilt-in-space and recline angles in people with spinal cord injury.
To compare the efficacy of wheelchair tilt-in-space and recline on enhancing muscle and skin perfusion over the ischial tuberosities in people with spinal cord injury (SCI). Repeated-measures and before-after trial design. University research laboratory. Power wheelchair users with SCI (N=20). Six combinations of wheelchair tilt-in-space and recline angles were presented to participants in a random order. The testing protocol consisted of a baseline 5 minutes sitting with no tilt/recline and 5 minutes positioned in a tilted and reclined position at each of 6 conditions, including: (1) 15° tilt-in-space and 100° recline, (2) 25° tilt-in-space and 100° recline, (3) 35° tilt-in-space and 100° recline, (4) 15° tilt-in-space and 120° recline, (5) 25° tilt-in-space and 120° recline, and (6) 35° tilt-in-space and 120° recline. Muscle and skin perfusion were assessed by near-infrared spectroscopy and laser Doppler flowmetry, respectively. Muscle perfusion was significantly increased at 25° and 35° tilt-in-space when combined with 120° recline, and skin perfusion was significantly increased at 3 tilt-in-space angles (15°, 25°, 35°) when combined with 120° recline and at 35° tilt-in-space when combined with 100° recline (P<.05). Even in the positions of increased muscle perfusion and skin perfusion (25° and 35° of tilt-in-space combined with 120° of recline), the amount of muscle perfusion change was significantly lower than the amount of skin perfusion change (P<.05). Our results indicate that a larger angle of tilt-in-space and recline is needed to improve muscle perfusion compared with skin perfusion. A position of 25° tilt-in-space combined with 120° recline is effective in enhancing muscle and skin perfusion of weight-bearing soft tissues at the ischial tuberosities.


Video-assisted thoracoscopic surgery lobectomy might be a feasible alternative for surgically resectable pathological N2 non-small cell lung cancer patients.
The majority of previous studies of the clinical outcome of video-assisted thoracoscopic surgery (VATS) versus open lobectomy for pathological N2 non-small cell lung cancer (pN2 NSCLC) have been single-center experiences with small patient numbers. The aim of this study was therefore to investigate these procedures but in a large cohort of Chinese patients with pathological N2 NSCLC in real-world conditions. Patients who underwent lobectomy for pN2 NSCLC by either VATS or thoracotomy were retrospectively reviewed from 10 tertiary hospitals between January 2014 and September 2017. Perioperative outcomes and overall survival of the patients were analyzed. Cox regression analysis was performed to identify potential prognostic factors. Propensity-score analysis was performed to reduce cofounding biases and compare the clinical outcomes between both groups. Among 2144 pN2 NSCLC, 1244 patients were managed by VATS and 900 by open procedure. A total of 305 (24.5%) and 344 patients died during VATS and the thoracotomy group during a median follow-up of 16.7 and 15.6 months, respectively. VATS lobectomy patients had better overall survival when compared with those undergoing the open procedure (P < 0.0001). Multivariate COX regression analysis showed VATS lobectomy independently favored overall survival (HR = 0.75, 95% CI: 0.621-0.896, P = 0.0017). Better perioperative outcomes, including less blood loss, shorter drainage time and hospital stay, were also observed in patients undergoing VATS lobectomy (P < 0.05). After propensity-score matching, 169 patients in each group were analyzed, and no survival difference were found between the two groups. Less blood loss was observed in the VATS group, but there was a longer operation time. VATS lobectomy might be a feasible alternative to conventional open surgery for resectable pN2 NSCLC. Significant findings of the study: VATS lobectomy has comparative OS in pN2 NSCLC versus open procedure in resectable patients. VATS lobectomy might be feasible for pN2 NSCLC.


Human endothelial cell cultures: phenotypic modulation by leukocyte interleukins.
We report here that soluble factors from activated mononuclear leukocytes have a dramatic effect on cultured endothelial cells. While human umbilical vein endothelial cells grown under standard conditions show a polygonal, epithelial-like morphology, cells exposed to culture media conditioned by lectin-activated human mononuclear leukocytes become extremely elongated and/or send out numerous cytoplasmic processes, assuming a dendritic configuration. This effect cannot be mimicked by exogenous cyclic AMP, is reversible upon interruption of the treatment, and appears specific for endothelial cells, since it has not been observed so far with other cell types. The shape changes are accompanied by a reorganization of the endothelial cell cytoskeleton: actin microfilament bundles tend to be disposed in parallel arrays, while intermediate filaments and microtubules penetrate up to the extremity of the cytoplasmic processes. Colchicine prevents endothelial cell elongation but only slightly impairs the formation of lateral cell processes ("dendritic configuration"). Purified interleukins were tested for their ability to induce these changes of cell shape. Escherichia coli-recombinant human interleukin 2 had no effect, and gamma-interferon only a slight effect on endothelial cell morphology. Interleukin 1 induced moderate cell elongation, while combined treatment with both interleukin 1 and gamma-interferon resulted in shape changes indistinguishable from those elicited by supernatants of activated mononuclear leukocytes. The possible relevance of the observed endothelial cell changes to the reported angiogenic activity of mononuclear cell products is discussed.


Safety concerns and multidisciplinary management of the dysphagic patient.
The interdisciplinary health care team is responsible for providing medical care based on a patient-centered model while maintaining professional and ethical standards. However, an emerging body of research suggests that ineffective and inappropriate care, or fatal errors, arise from the lack of productive communication between patients, families, and medical caregivers. This has prompted the evolution of a new health care discipline, patient safety, which became increasingly prominent in the 1990s. The purpose of this article is to bridge the gap between the discipline of patient safety and its relationship to the diagnosis of dysphagia.


Beneficial effects of glycocholic acid (GCA) on gut mucosal damage in bile duct ligated rats.
In order to investigate the effect of bile acids on gastrointestinal inflammations, bile duct ligated rats (BDL) were treated with GCA (25 mM/ml, oral or colonic) or saline I h before ethanol challenge and twice daily for 3 days in the ileitis group, while GCA was given twice daily for 3 days in the colitis group. BDL reduced the macroscopic and microscopic damage scores in the ileitis group compared to sham operated group, while it had no significant effect on ulcer or colitis groups. However, GCA given in BDL group reduced the ulcer index and microscopic damage in colitis group compared to saline-treated groups, but had no effect in ileitis group. Both BDL and GCA administration in BDL group reduced ileitis- or colitis-induced elevations in MPO levels. GCA administration in BDL group inhibited gastric acid output and volume. Our results suggest that oral or colonic administration of primary bile acids may be useful for the treatment of gastrointestinal inflammations.


Vascularisation and osteochondrosis of the epiphyseal growth cartilage of the distal femur in pigs--development with age, growth rate, weight and joint shape.
Until recently, the cartilage canals of the epiphyseal growth cartilage have not been associated with any specific disease. However, data support the hypothesis that osteochondrosis could be related to inadequate blood supply from vessels in these channels. We have done a study to investigate the relationship between the regression of cartilage canals and the formation of osteochondrosis latens in the epiphyseal growth cartilage of the distal femur in pigs, and the relationship between these events and age, growth rate, weight and femoral shape of the individual animals. This involved, in part, a comprehensive study of the distribution and pattern of regression of the cartilage canals. We found that the regression is a highly predictable process that follows an age-dependent pattern. However, we failed to prove any association between overall vascular regression and osteochondrosis, between vascular regression and weight, growth rate or femoral shape or between osteochondrosis and weight, growth rate or femoral shape. This may indicate that osteochondrosis latens is not caused by a general failure of vascular supply or general factors such as growth rate, but rather a consequence of local conditions affecting a limited number of vessels. A factor fitting this description is local compression.


Rat pancreas adenylate cyclase. VI. Role of the enzyme in secretin stimulated enzyme secretion.
1. The responsiveness of adenylate cyclase and enzyme secretin for secretin and the C-terminal octapeptide of pancreozymin has been investigated in particulate fractions of the pancreas of five different species. 2. The adenylate cyclase is sensitive to the C-terminal octapeptide of pancreozymin in all species investigated. 3. The enzyme is much more sensitive to secretin in rat and cat than in mouse and rabbit, whereas with guinea pig intermediate values are obtained. 4. The enzyme secretion is stimulated by secretin in pancreatic fragments of rat and cat, but not in those of mouse and rabbit. 5. These results suggest that in species where secretin stimulated enzyme secretion, it does so by stimulating the adenylate cyclase system.


Engineering a growth sensor to select intracellular antibodies in the cytosol of mammalian cells.
Intracellular antibodies (intrabodies) are expected to function as therapeutics as well as tools for elucidating in vivo function of proteins. In this study, we propose a novel intrabody selection method in the cytosol of mammalian cells by utilizing a growth signal, induced by the interaction of the target antigen and an scFv-c-kit growth sensor. Here, we challenge this method to select specific intrabodies against rabies virus nucleoprotein (RV-N) for the first time. As a result, we successfully select antigen-specific intrabodies from a naïve synthetic library using phage panning followed by our growth sensor-based intracellular selection method, demonstrating the feasibility of the method. Additionally, we succeed in improving the response of the growth sensor by re-engineering the linker region of its construction. Collectively, the described selection method utilizing a growth sensor may become a highly efficient platform for selection of functional intrabodies in the future.


Assessment of a Combined Panel of Six Serum Tumor Markers for Lung Cancer.
We have previously identified six serum tumor markers (TMs) (carcinoembryonic antigen, carbohydrate antigen 15.3, squamous cell carcinoma-associated antigen, cytokeratin-19 fragment, neuron-specific enolase, and pro-gastrin-releasing peptide) related to the presence of lung cancer (LC). To validate their individual performance in an independent cohort, and to explore if their combined assessment (≥1 abnormal TM value) is a more accurate marker for LC presence. We determined these six TMs in 3,144 consecutive individuals referred to our institution by their primary care physician because of the clinical suspicion of LC. LC was excluded in 1,316 individuals and confirmed in 1,828 patients (1,563 with non-small cell LC and 265 with small cell LC). This study validated the previously reported performance of each individual TM. We also showed that their combined assessment (≥1 abnormal TM) had a better sensitivity, specificity, negative predictive value, and positive predictive value (88.5, 82, 83.7, and 87.3%, respectively) than each TM considered individually and that it increased the diagnostic performance (area under the curve) of a clinical model that included tumor size, age, and smoking status. In patients with radiographic nodules less than 3 cm, the negative predictive value of the TM panel was 71.8%, hence providing some support for a more conservative diagnostic approach. Finally we identified two TMs (neuron-specific enolase and pro-gastrin-releasing peptide) that differentiate the risk of non-small cell LC from that of small cell LC. The combined assessment of a panel of six serum TMs is a more accurate marker for LC presence than these same TMs considered individually. The potential of these TMs in the diagnostic and screening settings deserves further research.


Efficacy and safety of intravenous pulsatile gonadotropin-releasing hormone: Lutrepulse for injection.
A multicenter trial was undertaken to assess the ability of pulsatile gonadotropin-releasing hormone to restore physiologic ovulatory function in women with diminished or absent pulsatile gonadotropin-releasing hormone secretion. In 109 women with primary and secondary hypothalamic amenorrhea, pulsatile gonadotropin-releasing hormone (Lutrepulse [gonadorelin acetate] for Injection) was extremely effective, resulting in ovulation in 91% and 96% of patients, respectively. Overall complications of intravenous line placement ranged from 0% to 11% (mean = 7%). A 12% incidence of multiple pregnancy was noted, and a single case of ovarian hyperstimulation was reported in a woman who also received clomiphene citrate. Pulsatile gonadotropin-releasing hormone treatment appears to be of at least comparable efficacy to human menopausal gonadotropins, with the added benefit of reduced overall risks for the patient with hypothalamic amenorrhea.


New ultra-fast algorithm for cochlear implant misalignment detection.
Postoperative imaging following cochlear implant (CI) placement is currently the only means of diagnosing proper electrode position. Manual multiplanar reconstruction (MPR) analysis of CT and CBCT is time-consuming and requires extensive training. This study aims to evaluate the rate of CI misalignment and to determine the amount of time necessary to reach a diagnosis of correct versus incorrect CI placement for readers of different experience levels, using a novel algorithm for image analysis (ACIR) compared to MPR analysis. The retrospective single centre study included 333 patients with cochlear implant surgery between May 2002 and May 2021. Postoperative CT and CBCT images were evaluated in three subgroups and the time to diagnosis was documented. Group 1: image evaluation using conventional MPR analysis; group 2: image evaluation by an experienced neuroradiologist via a novel ultra-fast algorithm; group 3: image evaluation by a young specialist via novel ultra-fast algorithm. T-test and Pearson's chi-squared test were used for inter-group comparisons. 333 patients (63.3 ± 15.9 years; 188 men) with 335 CIs were evaluated. The rate of CI misalignment diagnosed from 3D imaging was 14.3% (n = 48). MPR analysis required 255.7 ± 70.4 s per temporal bone, whereas Slicer plugin reduced analysis time to 83.3 ± 7.7 s (p < 0.001) for the experienced reader and 89.6 ± 8.7 s for the young specialist (p < 0.001). 3D postoperative imaging reveals high incidences of CI misalignment. Application of a novel ultra-fast algorithm significantly reduces the time for diagnosis compared to MPR analysis for readers of varying experience levels.


Protandry, synchronized flowering and sequential phenotypic unisexuality in neotropical Pentagonia macrophylla (Rubiaceae).
The neotropical shrub Pentagonia macrophylla Benth. (Rubiaceae) has protandrous two-day flowers. Synchronous development among flowers on a single individual results in sequential phenotypic unisexuality: the entire plant alternates gender from day to day. Pistillate flowers produce more nectar than staminate flowers at comparable hours, but this difference does not result in different paterns of visitation to male and female flowers by hummingbird pollinators. Rare periods of bisexuality occur due to asynchronous floral development within or between inflorescences and are always followed by return to a synchronized pattern of alternation of gender. Reestablishment of synchrony usually involves a timeframe shift in the pattern of flowering (i.e., a plant produces staminate flowers on days when it previously would have been pistillate). It is suggested that timeframe shifts occur in response to inadequate pollination and serve to either desynchronize the plant from neighboring conspecifics or to temporarily allow self-pollination.


Fabrication and characterization of high-performance forward-osmosis membrane by introducing manganese oxide incited graphene quantum dots.
Forward osmosis (FO) is the futuristic membrane desalination technology as it transcends the disadvantages of other pressure-driven techniques. But, there still remain critical challenges like fabrication of highly permeable membrane with ideal structures maintaining high rejection rates that need to be addressed for implementation as a practical technology. In this work, novel thin-film composite (TFC) membranes were fabricated by means of incorporating manganese oxide (MnO2) incited graphene quantum dots (GQDs) nanocomposite into a cellulose acetate (CA) suspension followed by phase inversion (PI) for enhanced FO performance. The surface morphology and chemical structure of fabricated membranes were studied using various characterization techniques like XRD, FT-IR, SEM-EDS, Mapping, AFM, and TGA. The structural parameters, water flux, reverse salt flux and salt rejection was estimated on the basis of data obtained from four varying initial draw solution concentrations. At high nanocomposites stacking, the hydrophilicity of the casting blend increase, and subsequently, the PI exchange rate additionally increases, which brings about noticeable difference in the surface morphology. The membrane with 0.5 wt% nanocomposite exhibited superior FO separation performance with osmotic water flux of 18.89, 34.49, 41.76 and 42.34 in L.m-2.h-1 with variable concentrations of NaCl salt solution (0.25M, 0.5M, 1M, and 2M), respectively. Also, the porosity of the membrane was increased to 47.23% with 96.87% salt rejection. The results indicate that the hydrophilicity of the nanocomposite drives them to the interface among CA and water during PI process leading to solid hydrogen bonding to achieve high water permeability.


Synthesis and isolation of polytrityl cations by utilizing hexaphenylbenzene and tetraphenylmethane scaffolds.
The successful isolation of stable (and soluble) hexa- and tetratrityl cations based on hexaphenylbenzene and tetraphenylmethane scaffold has been accomplished by using readily available starting materials. These robust polytrityl cations can be isolated in crystalline form and stored indefinitely at 0 degrees C. Their structures have been established by (1)H/(13)C NMR spectroscopy and by UV-vis spectroscopy. The structures of these polytrityl cations were further confirmed by quantitative transformations to the reduced (poly)triphenylmethyl derivatives by hydride transfer from triethylsilane, cycloheptatriene, or a borane-dimethyl sulfide complex.


Early detection of relapse after treatment for metastatic germ cell tumour of the testis: an exercise in medical audit.
The relapse patterns of 29 patients who recurred following treatment for metastatic germ cell tumours of the testis (seminoma n = 7, non-seminomatous germ cell tumour n = 22) have been analysed and the relative effectiveness of clinical follow-up and routine investigations in detecting relapse at an early stage have been examined. The analysis shows that routine estimation of the serum tumour markers human chorionic gonadotrophin and alpha-foetoprotein (HCG and AFP) is the single most important follow-up procedure. This is so, even in patients who were previously marker negative; it was the first indicator of relapse in 55% of the patients. Regular clinical examination and chest radiograph in asymptomatic patients was of little value. Chest radiograph gave the first evidence of relapse in only 2 cases (7%). The optimum frequency for follow-up computed tomographic scanning of the chest and abdomen remains debatable. In this series, it was the first abnormal investigation in 7 patients (24%) and proved to be particularly important in patients who had residual radiological abnormalities at the end of initial therapy. Cost analysis shows that intensive follow-up produces a total expenditure on investigations of approximately 4,500 pounds per relapse detected. Regular computed tomographic scanning is especially demanding on resources and costs approximately 12,880 pounds per relapse detected if the recommended protocol is followed.


X-radiation-induced chromosome breakage in retinoblastoma lymphocytes.
We have examined the spontaneous and X-radiation-induced chromosomal damage in normal humans and in patients with retinoblastoma using the BudR-Giemsa technique in lymphocytes cultured for 48 h. 9 sporadic unilateral non-hereditary cases, 11 hereditary cases (8 bilateral sporadic and 3 unilateral hereditary cases) and 20 healthy individuals were studied simultaneously. No difference in the spontaneous frequency of chromatid and chromosome aberrations was observed between patients and controls. After treatment with 150 rad the frequency of chromosome exchange aberrations was higher in unilateral hereditary cases than the controls (42.0% +/- 5.3 and 22.3% +/- 2.6 respectively; p = 0.05). In bilateral sporadic retinoblastoma 2 different groups were observed. A hypersensitive group showed a significant increment in radiation-induced chromosomal exchange aberrations over the control group (46.2% +/- 5.4 and 24.2% +/- 2.1 respectively; p = 0.01). The other group had a chromosomal exchange frequency similar to normal individuals (26.5% +/- 2.0 and 24.2% +/- 0.4 respectively; p = 0.10). Sporadic unilateral non-hereditary retinoblastoma had an exchange chromosomal aberration frequency similar to control individuals (26.1% +/- 2.8 and 24.6% +/- 2.7 respectively; p greater than 0.10). These results suggest that: There is no relationship between spontaneous chromosome fragility and retinoblastoma. Sporadic unilateral non-hereditary retinoblastoma has normal chromosome sensitivity to X-irradiation. Some hereditary cases of retinoblastoma are sensitive to X-rays while others behave like normals. A mutation or a submicroscopic deletion at a DNA repair locus which is independent of the retinoblastoma gene may cause this radiosensitivity.


Interpretation of canine liver biopsy. A clinician's perspective.
Proper evaluation of hepatic biopsies is essential for the proper management of dogs with liver disease. The clinician must have some basic knowledge of hepatic anatomy and histopathologic nomenclature in order to establish an accurate prognosis and therapeutic plan.


Mechanisms of stimulatory effects of mecamylamine on the dorsal raphe neurons.
Previous studies showed that mecamylamine a noncompetitive and nonspecific blocker of nicotinic acetylcholine receptors (nAChRs), stimulates the activity of the dorsal raphe nucleus (DRN) serotonergic neurons and DRN serotonin (5-HT) release. In the present study, the mechanisms involved in these mecamylamine-induced effects were examined using electrophysiology and calcium-imaging studies, both performed in Wistar rat midbrain slices. Mecamylamine (0.5-9 μM), bath administered, increased the firing frequency of identified 5-HT DRN neurons by a maximum of 5% at 3 μM. This effect was accompanied by a 112 % increase in the frequency of spontaneous excitatory postsynaptic currents of 5-HT DRN neurons. It was blocked by the AMPA/kainate receptor blocker CNQX (10 μM) and by the specific α4β2 nAChRs blocker dihydro-β-erythroidine (100 nM) but was not affected by tetrodotoxin (TTX, 500 nM). Simultaneously, mecamylamine produced a 58 % decrease in the frequency of GABAergic spontaneous inhibitory postsynaptic currents, an effect that was not influenced by TTX. Calcium-imaging studies support the results obtained with the electrophysiological studies by showing that mecamylamine (3 μM) increases the activity of a cell population located in the midline of the DRN, which was sensitive to the inhibitory effects of 8-OH-DPAT, an agonist at 5-HT1A receptors. It is assumed that mecamylamine, in low concentrations, acts as an agonist of α4β2 nAChRs present on the glutamatergic DRN terminals, thus increasing intra-raphe glutamate release. This stimulatory effect is reinforced by the decrease in DRN GABA release, which is dependent on the mecamylamine-induced blockade of α7 nAChRs located on DRN GABAergic terminals. We hypothesize that at least a part of mecamylamine antidepressant effects described in animal models of depression are mediated by an increase in DRN 5-HT release.


Video Interviewing: A Review and Recommendations for Implementation in the Era of COVID-19 and Beyond.
Due to the COVID-19 pandemic, it is very likely that many radiology residency and fellowship programs will adopt interactive videoconference interviewing for the 2020-2021 residency match cycle. Although video interviewing has become a common part of the hiring process for business, experience with video interviewing for resident and fellow selection has been limited. Advantages of video interviews over traditional on-site interviews include cost-savings to both applicants and residency programs, less disruption to an applicant's educational activities, and potential for training programs to access a wider pool of candidates. The loss of the casual interactions that occur during an on-site interview and the inability of candidates to evaluate training facilities and their surrounding environments in-person are among the obstacles posed by video interviews, but training programs can mitigate these challenges with enhanced website content and creative media solutions. Through a review of the existing literature and internet resources, this article recommends specific measures medical schools, applicants, and radiology residency and fellowship programs can take to optimize the virtual interview experience for all involved parties.


Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells.
From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.


Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1.
Niemann Pick C 1 (NPC1) disease is an incurable, devastating lysosomal-lipid storage disorder characterized by hepatosplenomegaly, progressive neurological impairment and early death. Current treatments are very limited and the research of new therapeutic targets is thus mandatory. We recently showed that the stimulation of adenosine A2A receptors (A2ARs) rescues the abnormal phenotype of fibroblasts from NPC1 patients suggesting that A2AR agonists could represent a therapeutic option for this disease. However, since all NPC1 patients develop severe neurological symptoms which can be ascribed to the complex pathology occurring in both neurons and oligodendrocytes, in the present paper we tested the effects of the A2AR agonist CGS21680 in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13 transiently transfected with NPC1 small interfering RNA). The down-regulation of the NPC1 protein effectively resulted in intracellular cholesterol accumulation and altered mitochondrial membrane potential. Both effects were significantly attenuated by CGS21680 (500 nM). The protective effects of CGS were prevented by the selective A2AR antagonist ZM241385 (500 nM). The involvement of calcium modulation was demonstrated by the ability of Bapta-AM (5-7 μM) in reverting the effect of CGS. The A2A-dependent activity was prevented by the PKA-inhibitor KT5720, thus showing the involvement of the cAMP/PKA signaling. These findings provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC disease.


The occurrence of fungi along the Red Sea coast and variability among isolates of Fusarium as revealed by isozyme analysis.
Nineteen identified species which belong to nine fungal genera were recovered from 14 samples collected from different sites of the Red Sea governorate. The aquatic fungal genera were Allomyces, Dictyuchus, Saprolegnia and Pythium while, the terrestrial fungal genera were Aspergillus, Penicillium, Fusarium, Neurospora and Rhizopus. Aspergillus was the most frequent genus, represented by seven species, of which A. niger, A. flavus and A. ustus were the most common. Penicillium was of occurred less frequently and was represented by two species, while Fusarium was isolated unfrequently and contributed four species. The remaining genera were unfrequent or rare and were each represented by one species. In addition, two electrophoretic isozyme patterns, esterase and glutamate oxalate transaminase (GOT), were determined to measure variability among 10 isolates of Fusarium. The results revealed that the tested fungi differed from each other in one or more esterase bands, except that F. moniliforme isolated from Safaga and from 40 Kilometers south of El-Kaussier yielded similar banding pattern. The activity of GOT was observed in the samples of F. solani and F. oxysporum and not detected in other isolates of Fusarium. The results indicated that F. solani differed from F. oxysporum in the isozymes of GOT, while no differences were observed between the isolated of the same species.


Crystal structure of d(CGCGAATTCGCG) complexed with propamidine, a short-chain homologue of the drug pentamidine.
The crystal structure of the complex between propamidine and the self-complementary DNA dodecamer d(CGCGAATTCGCG) duplex has been determined to a resolution of 2.1 A and a R-factor of 17.4%. The propamidine binds to the DNA within the minor groove, with specific hydrogen-bonding interactions from the amidinium groups to the bases and sugar groups of the DNA, via a 4-base-pair binding site. A network of water molecules lies over the mouth of the minor groove. The structure provides a rationale for the superior DNA-binding properties of propamidine as compared to pentamidine [cf. Edwards, K. J., Jenkins, T. C. & Neidle, S. (1992) Biochemistry 31, 7104-7109]. This is seen to result from (i) decreased minor groove width at the binding site and (ii) reduced mobility of the bound propamidine molecule.


Exploring shark VNAR antibody against infectious diseases using phage display technology.
Antibody with high affinity and specificity to antigen has widely used as a tool to combat various diseases. The variable domain of immunoglobulin new antigen receptor (VNAR) naturally found in shark contains autonomous function as single-domain antibody. Due to its excellent characteristics, the small, non-complex, and highly stable have made shark VNAR can acquires the antigen-binding capability that might not be reached by conventional antibody. Phage display technology enables shark VNAR to be presented on the surface of phage, allowing the exploration of shark VNAR as an alternative antibody format to target antigens from various infectious diseases. The application of phage-displayed shark VNAR in antibody library and biopanning eventually leads to the discovery and isolation of antigen-specific VNARs with diagnostic and therapeutic potential towards infectious diseases. This review provides an overview of the shark VNAR antibody, the types of phage display technology with comparison to the other types of display system, as well as the application and case studies of phage-displayed shark VNAR antibodies against infectious diseases.


Youth at ultra high risk for psychosis: using the Revised Network Episode Model to examine pathways to mental health care.
This paper aims to identify the ways in which youth at ultra high risk for psychosis access mental health services and the factors that advance or delay help seeking, using the Revised Network Episode Model (REV NEM) of mental health care. A case study approach documents help-seeking pathways, encompassing two qualitative interviews with 10 young people and 29 significant others. Theoretical propositions derived from the REV NEM are explored, consisting of the content, structure and function of the: (i) family; (ii) community and school; and (iii) treatment system. Although the aspects of the REV NEM are supported and shape pathways to care, we consider rethinking the model for help seeking with youth at ultra high risk for psychosis. The pathway concept is important to our understanding of how services and supports are received and experienced over time. Understanding this process and the strategies that support positive early intervention on the part of youth and significant others is critical.


Studies of stroke rehabilitation therapies should report blinding and rationalize use of outcome measurement instruments.
To review the reporting of key design features in studies of stroke rehabilitation therapies. We used purposive sampling to examine English-language, human-subject, comparative studies focusing on stroke rehabilitation therapy provided the effect of therapy was evaluated in at least one of the following six outcome domains: ambulation, cognition, quality of life, daily activities, dysphagia, or communication. We searched MEDLINE®, CINAHL®, PsycINFO®, and the Cochrane Database of Systematic Reviews (date range: January 2000 through late-January 2008) and extracted data from included studies using standardized forms. We depicted the extracted data in tables and summarized the findings qualitatively in the text. We retrieved 1,674 citations in the literature search and extracted data from 99 studies. Authors' reporting of key design features in stroke rehabilitation studies was lacking in four areas, that is, the background of persons delivering therapy, timing of therapy, subjects' receipt of prior or concomitant treatment, and psychometric properties of outcome measurement instruments. Except for four areas, reporting of key design features in studies of stroke rehabilitation therapies was quite comprehensive. Researchers should pay particular attention to reporting blinding, and they should rationalize the number of outcome measurement instruments used in their studies.


Direct in vitro and in vivo evidence for interaction between Hsp47 protein and collagen triple helix.
Hsp47 (heat shock protein 47), a collagen-specific molecular chaperone, is essential for the maturation of various types of procollagens. Previous studies have suggested that Hsp47 may preferentially recognize the triple-helix form of procollagen rather than unfolded procollagen chains in the endoplasmic reticulum. However, the underlying mechanism has remained unclear because of limitations in the available methods for detecting in vitro and in vivo interactions between Hsp47 and collagen. In this study, we established novel methods for this purpose by adopting a time-resolved FRET technique in vitro and a bimolecular fluorescence complementation technique in vivo. Using these methods, we provide direct evidence that Hsp47 binds to collagen triple helices but not to the monomer form in vitro. We also demonstrate that Hsp47 binds a collagen model peptide in the trimer conformation in vivo. Hsp47 did not bind collagen peptides that had been modified to block their ability to form triple helices in vivo. These results conclusively indicate that Hsp47 recognizes the triple-helix form of procollagen in vitro and in vivo.


Variation of pediatric and adolescents head and neck pathology in the city of Jeddah: A retrospective analysis over 10 years.
This study was conducted to present a comprehensive view of the most common head and neck pathologies among the pediatric and adolescent population of the city of Jeddah, Saudi Arabia. Data were collected from the oral and maxillofacial surgery (OMFS) records at King Abdulaziz University Hospital and King Fahad Hospital Jeddah (KFHJ) from the period 1998 to 2009. All patients who were 18 years of age and younger were included in the study. Identified lesions were classified into four categories: cystic, neoplastic, vascular and fibro-osseous. Age and sex distribution of the lesions were also calculated. A total of 155 patients were included in this study. Of all the lesions, 143 (92.26%) were benign and 12 (7.74%) were malignant; 63 (40.65%) were cysts; 48 (30.97%) were neoplasms; 23 (14.84%) were vascular and 21 (13.55%) were fibro-osseous tumors. The most common lesions were hemangioma (20 cases; 12.9%) followed by retention cyst (19 cases; 12.26%) and dentigerous cyst (15 cases; 9.68%). The most common benign odontogenic neoplasm was odontoma (7 cases; 4.52%), of which central giant cell granuloma (6 cases; 3.87%) was the most frequent benign nonodontogenic tumor and lymphoma (6 cases; 3.87%) was the most common malignant one. Although this study might benefit clinicians in guiding them through differential diagnosis of pediatric and adolescent head and neck pathology in reference to their sex and age groups, governmental efforts are badly needed to establish a Saudi childhood pathology registry.


Risk factors, microbiological profile, and treatment outcomes of pediatric microbial keratitis in a tertiary care hospital in Hong Kong.
To report the risk factors and microbiological profile of pediatric microbial keratitis cases in a tertiary care hospital in Hong Kong. Retrospective study. Case records of patients <18 years old with microbial keratitis were reviewed over a period of 10 years, between January 2001 and December 2010. Risk factors, microbiological profile, and treatment outcomes were analyzed. Overall, 18 patients (13 female, 5 male) with unilateral microbial keratitis were included. The mean age was 12.4 years (range: 3-17 years). The most commonly associated risk factor was contact lens wear (15, 83.3%). Seven cases (38.8%) were associated with orthokeratology lenses. Two cases (11.1%) were related to intrinsic keratopathy and 1 case (5.5%) was infected secondary to trauma. Microbiological culture was positive in 16 cases (88.8%). Overall, Pseudomonas sp. was the most commonly isolated organism (10/16, 62.5%), followed by coagulase-negative Staphylococcus (5/16, 31.2%) and Corynebacterium sp. (2/16, 12.5%). All cases responded to intensive medical management with topical antibiotics. One case with posttraumatic keratitis required stepped surgeries with initial tectonic penetrating keratoplasty followed by lens aspiration and retinal detachment repair. At the last follow-up, 13 out of 17 eyes (76.5%) had best-corrected visual acuity ≥20/40. Contact lens wear was the most commonly encountered risk factor for the occurrence of microbial keratitis in the pediatric age group in our setting. Orthokeratology remains one of the leading causes of contact lens-related infections. The majority of the cases responded to medical management.).


Commercial Air Travel for Passengers With Cardiovascular Disease: Stressors of Flight and Aeromedical Impact.
The exponential growth of commercial flights has resulted in a sharp rise of air travellers over the last 2 decades, including passengers with a wide range of cardiovascular conditions. Notwithstanding the ongoing COVID-19 pandemic that had set back the aviation industry for the next 1 to 2 years, air travel is expected to rebound fully by 2023-2024. Guidelines and evidence-based recommendations for safe air travel in this group vary, and physicians often encounter situations where opinions and assessments on fitness for flights are sought. This article aims to provide an overview of the stressors of commercial passenger flights with an impact on cardiovascular health for the general cardiologist and family practitioner, when assessing the suitability of such patients for flying fitness.


Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway.
Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor-associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear. Proteins and mRNA expression were determined by western blot and RT-qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo. First, we determined that lactate upgraded the M2-type polarization marker levels of macrophages. Cell function assays confirmed that lactate-activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor - oxamate hampered the level of lactate in TE-1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate-stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate-induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization. EC-secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC.


Nucleobindin 1 caps human islet amyloid polypeptide protofibrils to prevent amyloid fibril formation.
Many human diseases are associated with amyloid fibril deposition, including type 2 diabetes mellitus where human islet amyloid polypeptide (hIAPP) forms fibrils in the pancreas. We report here that engineered, soluble forms of the human Ca(2+)-binding protein nucleobindin 1 (NUCB1) prevent hIAPP fibril formation and disaggregate preexisting hIAPP fibrils. Scanning transmission electron microscopy (STEM) and atomic force microscopy indicate that NUCB1 binds to and stabilizes heterogeneous prefibrillar hIAPP species. The NUCB1-stabilized prefibrillar species were isolated by size-exclusion chromatography and analyzed by STEM, dynamic light scattering, and multi-angle light scattering. The stabilized prefibrillar species show a size range of 2-6 million Da and have other similarities to hIAPP protofibrils, but they do not progress to become mature fibrils. The effects of NUCB1 are absent in the presence of Ca(2+). We postulate that the engineered forms of NUCB1 prevent hIAPP fibril formation by a mechanism where protofibril-like species are "capped" to prevent further fibril assembly and maturation. This mode of action appears to be different from other protein-based inhibitors, suggesting that NUCB1 may offer a new approach to inhibiting amyloid formation and disaggregating amyloid fibrils.


The impact of smartphone use on learning effectiveness: A case study of primary school students.
This study investigated the effects of smartphone use on the perceived academic performance of elementary school students. Following the derivation of four hypotheses from the literature, descriptive analysis, t testing, one-way analysis of variance (ANOVA), Pearson correlation analysis, and one-way multivariate ANOVA (MANOVA) were performed to characterize the relationship between smartphone behavior and academic performance with regard to learning effectiveness. All coefficients were positive and significant, supporting all four hypotheses. We also used structural equation modeling (SEM) to determine whether smartphone behavior is a mediator of academic performance. The MANOVA results revealed that the students in the high smartphone use group academically outperformed those in the low smartphone use group. The results indicate that smartphone use constitutes a potential inequality in learning opportunities among elementary school students. Finally, in a discussion of whether smartphone behavior is a mediator of academic performance, it is proved that smartphone behavior is the mediating variable impacting academic performance. Fewer smartphone access opportunities may adversely affect learning effectiveness and academic performance. Elementary school teachers must be aware of this issue, especially during the ongoing COVID-19 pandemic. The findings serve as a reference for policymakers and educators on how smartphone use in learning activities affects academic performance.


Efficacy of add-on Danhong injection in patients with unstable angina pectoris: A double-blind, randomized, placebo-controlled, multicenter clinical trial.
Danhong injection (DHI),which is extracted from Salviae miltiorrhizae and Flos carthami,has been widely prescribed to patients with unstable angina pectoris (UAP) in China. However, a high quality clinical trial is needed. To determine whether DHI can relieve symptoms of transient myocardial ischemia in patients with unstable angina pectoris. A double-blind, placebo-controlled, randomized clinical trial was conducted in nine hospitals in China. Inpatients with UAP with blood stasis syndrome (BSS) were randomized 1:1 to receive DHI or placebo. The primary outcome was improvement rate in the quantification score of angina pectoris. Secondary outcomes included blood stasis syndrome scale, nitrates use, electrocardiogram recordings, PCI procedures, Seattle Angina Questionnaire (SAQ) and biochemical indexes. 160 participants were enrolled and 159 were analyzed. There was no significant difference in primary outcome as compared with control group at the end of 7-day treatment, but significant difference at 28-day follow up (70.53% [95% CI, 59.97-81.09%] and 54.34% [95% CI, 42.68-65.99%]; P = 0.0423). The BSS score was significantly lower in the DHI group than that in the control group at day 28 (6.49 [6.96] vs 10.53 [9.07], P = 0.0034). In addition, DHI was significantly superior to placebo in the angina stability score of SAQ (91.10 [17.37] versus 78.21 [22.08], P < 0.001). There were no significant differences in other secondary outcome measures. A small decrease in the total effective rate and an increase in the angina stability score were observed 28 days after implementation of DHI in UAP with a total blood stasis syndrome score decrease, but the efficacy was not observed at day 7. The findings support that DHI may potentially relieve clinical symptoms and can benefit angina stability. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02007187.


Exacerbation of wood smoke-induced acute lung injury by mechanical ventilation using moderately high tidal volume in mice.
We investigated the effects of mechanical ventilation with a moderately high tidal volume (VT) on acute lung injury (ALI) induced by wood smoke inhalation in anesthetized mice. Animals received challenges of air, 30 breaths of smoke (30SM) or 60 breaths of smoke (60SM) and were then ventilated with a VT of 10 ml/kg (10VT) or 16 ml/kg (16VT). After 4-h mechanical ventilation, the bronchoalveolar-capillary permeability, pulmonary infiltration of inflammatory cells, total lung injury score and pulmonary expressions of interleukin-1beta and macrophage inflammatory protein-2 mRNA and proteins in the 30SM+16VT and 60SM+16VT groups were greater than those in the 30SM+10VT and 60SM+10VT groups, respectively. Additionally, the wet/dry weight ratio of lung tissues and lung epithelial cell apoptosis in the 60SM+16VT group were greater than those in the 60SM+10VT group. These differences between the 16VT and 10VT groups were not seen in animals with air challenge. Thus, mechanical ventilation with a moderately high VT in mice exacerbates ALI induced by wood smoke inhalation.


Using a computerized discharge summary data base check box for adverse drug reaction monitoring.
The Joint Commission on Accreditation of Healthcare Organizations and the Food and Drug Administration (FDA) have encouraged hospitals to develop mechanisms to improve reporting of adverse drug reactions (ADRs). Cook County Hospital, in Chicago, introduced a check box on a computerized discharge summary form on which the physician codes for ADRs occurring during admission. Review of the data base for a two-year period disclosed 162 well-documented ADRs, many times greater than those generated in FDA reports. The patterns of ADRs found, actions taken in response, and strengths and limitations of this system for ADR screening are reviewed. This semispontaneous screening and reporting method is found to be a valuable tool for a local hospital's ADR program, with great potential for involving physicians and providing local feedback on ADR rates.


On the future of thrombolytic therapy for acute myocardial infarction.
The beneficial effects of thrombolytic therapy in acute ischemic coronary syndromes, and particularly in acute myocardial infarction, are now well established. The limited efficacy and potentially life-threatening side effects of currently available thrombolytic agents, however, remain a problem. Available evidence suggests that the efficacy of coronary thrombolysis could be augmented either by shortening the time to treatment, by improvement of the potency and specificity of fibrin-dissolving agents, by optimized conjunctive treatment with anticoagulant and antiplatelet agents, or by a combination of all 3. These objectives can be pursued by intensified education of the public, paramedical personnel, and physicians; development of novel thrombolytic agents; and further elucidation of pathophysiologic determinants of recanalization and its maintenance. Although it is clear that compounds with antithrombin or antiplatelet properties may enhance and sustain the action of thrombolytic agents, their optimal use and potential hemorrhagic side effects remain to be further explored. Optimized thrombolytic therapy eventually will most likely consist of administration of potent specific plasminogen activators in combination with conjunctive targeted anticoagulant and/or antiplatelet agents.


Prospects and challenges for squeezing-enhanced optical atomic clocks.
Optical atomic clocks are a driving force for precision measurements due to the high accuracy and stability demonstrated in recent years. While further improvements to the stability have been envisioned by using entangled atoms, squeezing the quantum mechanical projection noise, evaluating the overall gain must incorporate essential features of an atomic clock. Here, we investigate the benefits of spin squeezed states for clocks operated with typical Brownian frequency noise-limited laser sources. Based on an analytic model of the closed servo-loop of an optical atomic clock, we report here quantitative predictions on the optimal clock stability for a given dead time and laser noise. Our analytic predictions are in good agreement with numerical simulations of the closed servo-loop. We find that for usual cyclic Ramsey interrogation of single atomic ensembles with dead time, even with the current most stable lasers spin squeezing can only improve the clock stability for ensembles below a critical atom number of about one thousand in an optical Sr lattice clock. Even with a future improvement of the laser performance by one order of magnitude the critical atom number still remains below 100,000. In contrast, clocks based on smaller, non-scalable ensembles, such as ion clocks, can already benefit from squeezed states with current clock lasers.


Efficacy of different surgical approaches on survival outcomes in patients with early-stage cervical cancer: protocol for a multicentre longitudinal study in China.
Recent studies have revealed that the oncological survival outcomes of minimally invasive radical hysterectomy (MIRH) are inferior to those of abdominal radical hysterectomy (ARH) in early-stage cervical cancer, but the potential reasons are unclear. Each expert from 28 study centres participating in a previously reported randomised controlled trial (NCT03739944) will provide successive eligible records of at least 100 patients who accepted radical hysterectomy for early-stage cervical cancer between 1 January 2009 and 31 December 2015. Inclusion criteria consist of a definite pathological evaluation of stages IA1 (with positive lymphovascular space invasion), IA2 and IB1 according to the International Federation of Gynecology and Obstetrics 2009 staging system and a histological subtype of squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma. The primary endpoint is 5-year disease-free survival between the MIRH and ARH groups. The secondary endpoints include the MIRH learning curves of participating surgeons, 5-year overall survival between the MIRH and ARH groups, survival outcomes according to surgical chronology, surgical outcomes and sites of recurrence and potential risk factors that affect survival outcomes. A subgroup analysis in patients with tumour diameter less than 2 cm will follow the similar flow diagram. This study has been approved by the Institutional Review Board of Peking Union Medical College Hospital (registration no. JS-1711), and is also filed on record by all other 27 centres. The results will be disseminated through community events and peer-reviewed journals. NCT03738969.


Immunohistochemical studies of C-reactive protein and apolipoprotein B in inflammatory and arterial lesions.
Interactions in vivo between C-reactive protein (CRP) and apolipoprotein B (apo-B)-containing lipoproteins were sought in inflammatory lesions and atherosclerosis. CRP was demonstrated immunohistochemically on the surface of some muscle fibres in locally induced inflammatory lesions in the rabbit, but apoB was not detected in the same distribution. CRP was not detected in catheter-induced aortic endothelial injuries in the rabbit, in arterial lesions containing apoB from cholesterol-fed rabbits, in apoB-containing human fatty streaks or in advanced human atherosclerotic lesions.


[Intravitreal application of triamcinolone--our experiences].
To show the results of intravitreal application of triamcinolone used as a primary or adjuvant therapy. We analyzed 48 patients with different ocular disorders: exudative age related macular degeneration, diabetic retinopathy, or central retinal vein occlusion. We analyzed color fundus photography, visual acuity, fluorescein angiography and complications of intravitreal triamcinolone application. There was a marked reduction of macular edema in 70% of patients verified on fluorescein angiography. Visual acuity improved in 62% of patients. The most common complication was transient rise in intraocular pressure. There was no case of endophthalmitis. Intravitreal application of triamcinolone is relatively safe and efficacious in selected patiens with different ocular disorders.


Temporal Integration of Auditory Information Is Invariant to Temporal Grouping Cues
Auditory perception depends on the temporal structure of incoming acoustic stimuli. Here, we examined whether a temporal manipulation that affects the perceptual grouping also affects the time dependence of decisions regarding those stimuli. We designed a novel discrimination task that required human listeners to decide whether a sequence of tone bursts was increasing or decreasing in frequency. We manipulated temporal perceptual-grouping cues by changing the time interval between the tone bursts, which led to listeners hearing the sequences as a single sound for short intervals or discrete sounds for longer intervals. Despite these strong perceptual differences, this manipulation did not affect the efficiency of how auditory information was integrated over time to form a decision. Instead, the grouping manipulation affected subjects' speed-accuracy trade-offs. These results indicate that the temporal dynamics of evidence accumulation for auditory perceptual decisions can be invariant to manipulations that affect the perceptual grouping of the evidence.


Familial aplasia or hypoplasia of the patella.
A father with bilateral absence of the patella and his son with pronounced hypoplasia of the patellae are described. A possible relationship between this syndrome and hereditary osteo-onycho-dysplasia is discussed.


Midterm outcomes of femoral arteries after percutaneous endovascular aortic repair using the Preclose technique.
Percutaneous access during endovascular aortic repair has been shown to be feasible and safe using a suture-mediated closure device ("Preclose" technique) for closure of up to 24F introducer sheaths. The purpose of this study is to examine the late outcomes of those femoral arteries repaired in this manner. The Preclose technique has been previously described. Briefly, the technique involves two Perclose Proglide devices deployed in the femoral artery prior to insertion of the large diameter introducer sheath and then closure of the arteriotomy by tying down knots of the Proglide following removal of the sheath. The medical records of all patients who underwent endovascular aortic repairs using the Preclose technique between December 2004 and August 2007 were reviewed. Follow-up protocol consisted of computed tomography (CT) angiograms performed at 1, 6, and 12 months, and annually thereafter. All Preclose patients who had at least a 6-month postoperative scan were included in the study. For each patient, the most recent postoperative scan was compared with the preoperative scan for evidence of any new anatomic abnormalities of the femoral artery such as dissection, stenosis, or pseudoaneurysm. Three-dimensional post processing with multiplanar reconstructions was also performed as necessary to confirm axial scan findings. A total of 292 patients underwent percutaneous endovascular aortic repairs (TEVAR-125, EVAR-167). Four hundred thirty-two femoral arteries were closed with 870 devices. Four hundred eighteen vessels were approximated with two devices, while 30 arteries required three devices for hemostasis and an additional four vessels only required a single device. Two hundred seventy-eight (64.3%) vessels were accessed with sheaths 18 to 24F. Four hundred eight femoral arteries (94.4%) were closed successfully with the Preclose technique. There were 100 patients (TEVAR-35, EVAR-65) who had adequate postoperative CT scan at 6-months or later. The mean follow up was 11.6 +/- 5.0 months. Of the 156 femoral arteries in these 100 patients repaired using the Preclose technique, there were 3 late complications in 3 patients, 1 asymptomatic femoral artery dissection, and 2 femoral artery pseudoaneurysms requiring surgical repair, resulting in a late complication rate of 1.92% (3/156). Percutaneous closure of femoral arteries after large diameter introducer sheaths using the Preclose technique has a low incidence of early and late complications related to the closure site.


Nutritional cancer risks derived from energy and fat.
Both animal and human studies indicate that increased caloric intake and increases in body weight and obesity are associated with increased risk of cancer of the breast, endometrium, ovaries, colon, rectum and prostate. Recent animal studies indicate that it is the total caloric intake, rather than the percent of fat in the diet, that is associated with tumorigenesis and carcinogenesis, and that tumor development depends on a complex interaction involving energy intake, energy expenditure, energy retention within the body (body fat vs lean body mass) and body size. Omega-3 fatty acids inhibit tumorigenesis and tumor growth in many cancer models in rodents. Exercise diminishes tumor formation in mice, rats and humans. Exercise delays mortality from all causes, and life-long exercise is associated with decreased cancers of the breast and reproductive system in women, and cancer of the colon in women and men.


Associations between physical and psychosocial work environment factors and sickness absence incidence depend on the lengths of the sickness absence episodes: a prospective study of 27 678 Danish employees.
This study examined if the association between work environment factors and sickness absence (SA) depended on the inclusion or exclusion of short-term SA episodes. We linked the 'Work Environment and Health in Denmark' survey with the 'Danish Register of Work Absences' (n=27 678). Using covariate adjusted Cox regression, we examined the associations between work environment factors and SA by changing the cut-off points for the length of the SA episodes, for example, episodes ≥1 day, ≥6 days and ≥21 days. We examined three physical work environment factors: 'Back bend or twisted', 'Lifting or carrying', 'Wet hands' and three psychosocial work environment factors: 'Poor influence', 'Role conflicts' and 'Bullying'. 'Back bend or twisted' and 'Lifting or carrying' had small significant HRs for SA episodes ≥1 day and large and highly significant HRs for SA episodes ≥6 days and ≥21 days. 'Wet hands' had small significant HRs for SA episodes ≥1 day for both sexes and large and highly significant HR for ≥6 days for women. HRs of all three psychosocial factors were highly significant for SA episodes ≥1 day and ≥6 days for both sexes, and 'Poor influence' and 'Role conflicts' were significant for SA episodes ≥21 days for women. The physical work factors had higher associations with SA when SA episodes of 1-5 days were excluded and focus was on SA episodes ≥6 days. The psychosocial work factors were strongly associated with SA both with and without SA episodes of 1-5 days included in the analyses.


Increased serum concentration of nerve growth factor in patients with microprolactinoma.
Nerve growth factor (NGF) is known to play a role as a circulating neurokine, integrating signals from the neuro-immuno-endocrine system. The ability of NGF to activate the pituitary-adrenocortical axis, together with the increase of its serum concentration in pregnancy and lactation, supports the hypothesis that NGF is secreted by the pituitary gland and plays a role as modulator of endocrine functions. Evidence obtained both in vitro and in vivo in experimental animal models suggests that lactotroph cells secrete both prolactin (PRL) and NGF. Furthermore, in previous studies we demonstrate that cell lines derived from dopamine (DA)-sensitive human prolactinomas express high levels of NGF messenger RNA and protein. On these basis, we studied serum NGF concentrations in female patients with microprolactinoma (n = 4) and in control women (n = 5). PRL and NGF were measured at the diagnosis, during the thyrotropin releasing hormone (TRH) test and after the therapy with DA D2 receptor agonist cabergoline (0.25 mg, twice a week). Results obtained suggested that hyperprolactinemia (70.3+/-8.4 ng/ml) paralleled markedly higher NGF levels (58.4+/-18.7 pg/ml) compared to controls (PRL 8.7+/-3.2 ng/ml, NGF 8.4+/-1.3 pg/ml). Serum concentrations of NGF and PRL during the TRH test were closely associated (r = 0.943, p < 0.01). Cabergoline therapy normalized PRL (7.9+/-3.6 ng/ml) and induced a significant decrease of NGF levels (12.5+/-4.9 pg/ml). In conclusions, data reported here indicated that, in human microprolactinomas, NGF is released in the bloodstream paralleling PRL-secretion and it is modulated by a neurotransmitter-regulated mechanism, since the normalization of PRL elicited by the DA D2 receptor agonist cabergoline induced a significant decrease of serum NGF as well.


Discovery of phthalazino[1,2-b]-quinazolinone derivatives as multi-target HDAC inhibitors for the treatment of hepatocellular carcinoma via activating the p53 signal pathway.
In view of histone deacetylases (HDACs) as a promising target for cancer therapy, a series of phthalazino[1,2-b]-quinazolinone units were hybrided with ortho-aminoanilide or hydroxamic acid to serve as multi-target HDAC inhibitors for the treatment of solid tumors. Among the target compounds, 8h possessed nano-molar IC50 values toward the tested cancer cells and HDAC subtypes, which was more potent than the HDAC inhibitor SAHA (vorinostat). Mechanism study revealed that compound 8h could suppress the HepG2 cell proliferation via prompting the acetylation of histone 3 (H3) and α-tubulin, and activating the p53 signal pathway as designed. In addition, compound 8h exhibited much stronger in vivo antitumor efficacy than SAHA in the HepG2 xenograft tumor model with negligible toxicity. As a novel multi-target HDAC inhibitor, compound 8h deserves further development as a potential anticancer agent.