Epidemiological and immunological characteristics of childhood leukaemia in The Netherlands: population-based data from a nationwide co-operative group of paediatricians.
In this review results are presented from several population-based epidemiological and immunological studies of children with leukaemia in The Netherlands, who were diagnosed between 1973 and 1982 through a nationwide co-operative group of paediatricians. From 1973 till 1980 annual incidence rates appeared to be 3.1 per 10(5) person-yr. No significant trend was observed in this period. However a preliminary analysis of patients in the 1980-1982 period showed an increase. Mortality rates are decreasing since 1973, as expected. Incidence rates and proportions of different morphological and immunological subtypes reflect the pattern of occurrence in populations with a high standard of living. A relatively high incidence rate of acute lymphocytic leukaemia (ALL) is observed with a peak at the age of 3-5. The proportion of patients with T-cell phenotype among ALL-patients, immunologically typed between 1979 and 1982, appeared to increase with age, while the proportion of common ALL decreased. Statistical analysis of the data of patients with ALL in the Western part of the country including areas with nuclear plants, gave no indication for the presence of clustering. Subclassification of childhood leukaemia (CL), notably ALL, may be necessary for obtaining more specific etiologic clues. In view of the incidence of CL and ALL large scale, immunological and epidemiological investigations of CL, and the related non-Hodgkin's lymphomas, preferably population-based, are necessary.


Reactivity of mucohalic acids in water.
One group of disinfection byproducts of increasing interest are the halogenated furanones, which are formed in the chlorination of drinking water. Among these halofuranones is mucochloric acid (MCA, 3,4-dichloro-5-hydroxyfuran-2(5H)-one), and mucobromic acid (MBA, 3,4-dibromo-5-hydroxyfuran-2(5H)-one). Both mucohalic acids (MXA) are direct genotoxins and potential carcinogens, with the capacity to alkylate the DNA bases guanosine, adenosine and cytosine, and they have been measured in concentrations ranging up to 700 ng/l in tap water. MCA and MBA react in basic aqueous medium to form mucoxyhalic acids (4-halo-3,5-hydroxyfuran-2(5H)-one). Since: i) this reaction may represent the first step in the abiotic decomposition of mucohalic acids, ii) mucoxyhalic acids have been proposed as possible intermediates in the reaction of MXA with DNA, a kinetic study of the reaction mechanism is of interest. Here, the following conclusions were drawn: a) At moderately basic pH, the reaction of mucohalic acids with OH(-) to form mucoxyhalic acids is kinetically significant. b) The nucleophilic attack of hydroxide ions on MXA occurs through a combination of two paths: one of them is first-order in hydroxide whereas the other is second-order and are proposed to occur through the deprotonation of the hydrate of MXA. c) The hydration constants of mucohalic acids -0.23 and 0.17 for MCA and MBA respectively - corresponds to the very significant hydrate concentrations. Since hydrates are not electrophilic, these values imply a decrease in the alkylating capacity of mucohalic acids.


Rapid determination of X-ray contrast agent iomeprol in human plasma by on-line solid-phase extraction coupled with phase optimized liquid chromatography.
Phase optimized liquid chromatography (POPLC) allows for the optimized combination of column segments of any length and stationary phases with different functionalities. In this study, a simple and rapid method using POPLC coupled with on-line solid-phase extraction (SPE) for the analysis of X-ray contrast media agent iomeprol (IOM) in human plasma was developed. Because the phenyl (PH) stationary phase has strong hydrophobic and π-π interactions with IOM and iopromide (IOP, internal standard), the best separation efficiency was achieved with a 250mm×3mm homogenous PH POPLC-column. Different kinds of on-line SPE sorbents were studied, including restricted access material-alkyl diol silica (ADS), LiChrolut EN with excellent absorption capacity and hydrophilic-lipophilic-balanced Oasis HLB. The most efficient on-line sample clean-up was carried out using a fast-flow on-line purification approach with an Oasis HLB pre-column ((20mm×2mm, 30μm). This pre-column showed excellent durability and reproducibility. At least 400 samples could be analyzed with one pre-column. Each plasma sample was directly injected and analyzed within 15min. The calibration curves were linear in the range of 10-1000μg/mL. The limit of quantitation was 2.26μg/mL. The inter-day precision of this method was excellent and less than 1.44%, and the intra-day precision was less than 4.44%. The inter-day and intra-day accuracy ranged from 94.33% to 104.36% and 94.60% to 101.71%, respectively. This validated method is expected to be useful in the analysis of human plasma samples for glomerular filtration rate (GFR) measurements and assessment of kidney function.


Could fever and neuroinflammation play a role in the neurobiology of autism? A subject worthy of more research.
Autism is neuropsychiatric disorder in which a hyperglutamate state may play a role. It is suggested here that fever or hyperthermia may be able to alter glutamate levels in the brain and may therefore be able to impact on the symptoms of autism. More study on this possibility is clearly warranted.


Nuclear mutants of Neurospora crassa temperature-sensitive for the synthesis of cytochrome aa3. Mitochondrial protein synthesis and analysis of the polypeptide composition of cytochrome c oxidase.
Three previously isolated mutants of Neurospora crassa, temperature-sensitive for the production of cytochrome aa3, have been further analyzed. These mutants have a slightly reduced capacity for mitochondrial protein synthesis when grown at 41 degrees C, although this relative deficiency appeared to be no greater than the deficiency in other cytochrome-aa3-deficient mutants. Thermolability studies revealed that the cytochrome c oxidase purified from each of the mutants grown at 23 degrees C is no more sensitive to heat inactivation than the enzyme isolated from wild-type cells. Sodium dodecylsulfate gel electrophoresis of immunoprecipitates obtained from the mitochondria of each of the mutants grown at 23 degrees C, using antiserum directed against holocytochrome c oxidase, indicated that all the subunits of cytochrome c oxidase were present in relative amounts similar to those found in mitochondria from wild-type cultures. However, when the mitochondria from mutant cultures grown at 41 degrees C were examined in the above fashion, only subunits 5 and 6 of the oxidase were detected. Nonetheless, the mitochondrially synthesized subunit 1, 2 and 3 polypeptides could be immunoprecipitated from mitochondria isolated from mutant cells grown at 41 degrees C and labelled with [3H]leucine in medium containing cycloheximide. Although subunits 4 and 7 could not be detected, because a suitable antibody was not available, the fact that five of the seven subunits were present, but not associated with each other, suggested that the genetic defects in these mutants may affect the process of cytochrome c oxidase assembly.


Development and validation of a risk prediction nomogram for serious arrhythmias in acute digoxin toxicity among pediatrics: A multicenter study.
Digoxin is a cardiac glycoside obtained from the leaves of the foxglove plant, Digitalis lanata. Several studies have described the safety of digoxin including various life-threatening events, notably cardiac arrhythmias. Early identification of high-risk patients and subsequent initiation of the utmost medical care are associated with a better prognosis. The assessment of serum digoxin levels, which is not always convenient, is the only tool used to evaluate the severity of digoxin exposure. However, the feasibility of this tool, particularly in resource-restricted countries, remains unclear. Therefore, the current study aimed to establish and validate a feasible alternative tool, a bedside nomogram, to identify pediatric patients diagnosed with acute digoxin intoxication who are at risk of developing serious arrhythmias. This was a two-phase, multicenter, retrospective study. The prevalence of serious arrhythmias was approximately 17%. Patients diagnosed with serious arrhythmias showed significantly higher serum digoxin, random blood glucose, and potassium levels but lower sodium, magnesium, and hemoglobin levels. Serious arrhythmias were associated with significantly lower P-R intervals, shorter QTc intervals, and more frequent digoxin effects (p < 0.05). The proposed nomogram showed that combining age and initial random blood glucose, sodium, and potassium levels could predict the future incidence of serious arrhythmia with an accuracy of 96.2% (sensitivity = 94.4%, specificity = 96.5%), an area under the curve (AUC) of 0.977, and p < 0.001. Validation of the proposed nomogram yielded an AUC for the nomogram probability of approximately 81%, and the AUC for the predicted probability using the developed model was 98.3%, indicating that both the validated model and the developed nomogram were significant predictors of serious arrhythmia. The utility of using the four-factor nomogram to determine the risk of serious arrhythmia in children exposed to an overdose of digoxin is comparable, if not superior, to the serum digoxin level.


In vitro studies on resealed erythrocyte ghosts as protein carriers.
Resealed erythrocyte ghosts have been proposed as in vivo carriers for enzyme replacement therapy of inherited metabolic diseases. In comparative studies of methods for reversible hypotonic haemolysis of erythrocytes, a five-fold increased entrapment of human serum albumin was obtained by use of a dialysis procedure instead of direct dilution. The percentage incorporation of protein was also affected by varying mixing procedure, haematocrit, lysis, and resealing times but not by varying buffer composition or added protein concentrations over a wide range. Higher protein entrapment was observed with time-expired blood compared to fresh blood and this may be ascribed to increased osmotic fragility of the erythrocyte membrane in stored cells. Haemolysed and resealed ghosts prepared by any method used were smaller than normal erythrocytes as measured with a Coulter Counter and with a fluorescence-activated cell sorter, and protein entrapment reduced the ghost size further.


A rare case of lymphangiomyomatosis treated with leuprolide acetate: five-years follow-up.
Lymphangiomyomatosis (LAM) is a rare and systemic disease that is characterized by the abnormal proliferation of smooth muscle-like cells in the lungs and along the axial lymphatic system. The authors herein present a rare case of LAM that was treated with long-term use of leuprolide acetate, a gonadotropin-releasing hormone analogue (GnRHa).


A new extra sequence at the amino terminal of a mu heavy chain disease protein (DAG).
The primary structure of a human mu heavy chain (DAG) protein is described. The native protein is a circular decamer with a molecular weight (Mr) of 500 kDa, each decamer being constituted of the constant domains C mu 2, C mu 3 and C mu4 and interlinked by 15 disulfide bridges. At its NH2-terminal each monomeric chain starts with an "extra sequence". The amino acid sequence of this segment is Arg-Gln-Ser-Asp-Asp-Pro-Val-Leu-Arg-Gly-Thr-Thr-Val-Pro-Val-Thr-Glu and its reinitiation point is located at Val223 (Gal numbering), at the beginning of C mu 2. This sequence has no homology with any other protein included in the present databases.


Percutaneous transhepatic biliary drainage: alternatives in left hepatic duct obstruction.
The left-lobe subxiphoid approach has been the standard way to drain left hepatic duct occlusion. A new, right-side biliary drainage approach is described. Five patients, among 25 patients with bilateral biliary obstruction, were treated by an internal-internal drainage system. Three types of internal-internal drainage techniques are described: internal-internal luminal, type 1; internal-internal luminal, type 2; and internal-internal transductal, type 3. All 5 patients succeeded in biliary drainage. The internal-internal biliary drainage technique, performed from the right-side approach, is effective, avoids additional liver puncture and tract dilatation, and allows the combination of several biliary drainage techniques, adding greatly to the flexibility when treating intrahepatic obstruction. No complications were observed in our small series but special precaution should be taken with the transductal technique due to the possibility of bleeding.


Image analysis of small animal feeding behavior: an update.
Recently we published a design for an automated feeding behavior system (Rowley, Stitt, & Hanson, 2003). One disadvantage of this system is that it relied on expensive, custom hardware. Here we present a modified version that replaces the custom hardware with a simple, commercially available webcam and modified the MATLAB analysis software as well. The new system is much less expensive and easier to implement, while still providing for bias-free collection of consumption data in a feeding behavior trial.


Macrophyte and periphyton dynamics in a UK Cretaceous Chalk stream: the river Kennet, a tributary of the Thames.
An initial study to observe the seasonal trends and to determine the factors influencing macrophyte and periphyton growth patterns was undertaken on a representative reach of the River Kennet (UK) over a 2-year period (1998-2000). Maximum average macrophyte and average periphyton dry matter biomass recorded during the growing season were 200 and 21 g m(-2), respectively. The relationships between macrophyte and periphyton percentage cover and biomass data with physico-chemical variables were investigated. Regression analysis indicated that of the parameters measured, flow, and in the case of the dominant Ranunculus spp., solar radiation, were best able to predict macrophyte biomass and cover. The periphytic biomass within the reach was low, possibly as a result of relatively high flows and low phosphorus concentrations following the introduction of effluent treatment at the sewage works immediately upstream of the reach. Periphytic biomass was poorly correlated with the physical variables measured. This indicates that biomass is regulated by complex interactions between the physical and chemical factors, such as flow, solar radiation and phosphorus concentration. These interrelationships require further investigation.


Areas of cerebral blood flow changes on arterial spin labelling with the use of symmetric template during nitroglycerin triggered cluster headache attacks.
Cluster headache is a rare, strictly unilateral, severe episodic primary headache disorder. Due to the unpredictable and episodic nature of the attacks, nitroglycerin has been used to trigger attacks for research purposes to further our understanding of cluster headache pathophysiology. We aimed to identify regions of significant cerebral blood flow (CBF) changes during nitroglycerin triggered cluster headache attacks, using MRI with arterial spin labelling (ASL). Thirty-three subjects aged 18-60 years with episodic and chronic cluster headache were recruited and attended an open clinical screening visit without scanning to receive an intravenous nitroglycerin infusion (0.5 μg/kg/min over 20 min). Those for whom nitroglycerin successfully triggered a cluster headache attack, were invited to attend two subsequent scanning visits. They received either single-blinded intravenous nitroglycerin (0.5 μg/kg/min) or an equivalent volume of single-blinded intravenous 0.9% sodium chloride over a 20-minute infusion. Whole-brain CBF maps were acquired using a 3 Tesla MRI scanner pre-infusion and post-infusion. As cluster headache is a rare condition and purely unilateral disorder, an analysis strategy to ensure all the image data corresponded to symptomatology in the same hemisphere, without losing coherence across the group, was adopted. This consisted of spatially normalising all CBF maps to a standard symmetric reference template before flipping the images about the anterior-posterior axis for those CBF maps of subjects who experienced their headache in the right hemisphere. This procedure has been employed in previous studies and generated a group data set with expected features on the left hemisphere only. Twenty-two subjects successfully responded to the nitroglycerin infusion and experienced triggered cluster headache attacks. A total of 20 subjects completed the placebo scanning visit, 20 completed the nitroglycerin scanning visit, and 18 subjects had completed both the nitroglycerin and placebo scanning visits. In a whole-brain analysis, we identified regions of significantly elevated CBF in the medial frontal gyrus, superior frontal gyrus, inferior frontal gyrus and cingulate gyrus, ipsilateral to attack side, in CBF maps acquired during cluster headache attack; compared with data from the placebo session. We also identified significantly reduced CBF in the precuneus, cuneus, superior parietal lobe and occipital lobe contralateral to the attack side. Of particular interest to this field of investigation, both the hypothalamus and ipsilateral ventral pons showed higher CBF in a separate region of interest analysis. Our data demonstrate that severe cluster headache leads to significant increases in regional cerebral perfusion, likely to reflect changes in neuronal activity in several regions of the brain, including the hypothalamus and the ventral pons. These data contribute to our understanding of cluster headache pathophysiology; and suggest that non-invasive ASL technology may be valuable in future mechanistic studies of this debilitating condition.


Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression.
Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. In cancer patients HA concentrations are usually higher in malignant tumors than in corresponding benign or normal tissues, and in some tumor types the level of HA is predictive of malignancy. HA is often bound to CD44 isoforms which are ubiquitous, abundant, and functionally important cell surface receptors. This article reviews the current evidence for HA/CD44-mediated activation of the ankyrin-based cytoskeleton and RhoGTPase signaling during tumor progression. A special focus is placed on the role of HA-mediated CD44 interaction with unique downstream effectors (e.g., the cytoskeletal protein, ankyrin and/or various GTPases (e.g., RhoA, Rac1 and Cdc42)) in coordinating intracellular signaling pathways (e.g., Ca(2+) mobilization, Rho signaling, PI3 kinase-AKT activation, NHE1-mediated cellular acidification, transcriptional upregulation and cytoskeletal function) and generating the concomitant onset of tumor cell activities (e.g., tumor cell adhesion, growth, survival, migration and invasion) and tumor progression. I believe this information will provide valuable new insights into poorly understood aspects of solid tumor malignancy. Furthermore, the new knowledge concerning HA/CD44-mediated oncogenic signaling events will have potentially important clinical utility, and could establish CD44 and its associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential. It could also serve as ground work for the future development of new drug targets to inhibit HA/CD44-mediated tumor metastasis and cancer progression.


The human oviduct transcriptome reveals an anti-inflammatory, anti-angiogenic, secretory and matrix-stable environment during embryo transit.
The human oviduct serves as a conduit for spermatozoa in the peri-ovulatory phase and nurtures and facilitates transport of the developing embryo for nidation during the luteal phase. Interactions between the embryo and oviductal epithelial surface proteins and secreted products during embryo transit are largely undefined. This study investigated gene expression in the human oviduct in the early luteal versus follicular phases to identify candidate genes and biomolecular processes that may participate in maturation and transport of the embryo as it traverses this tissue. Oviductal RNA was hybridized to oligonucleotide arrays and resulting data were analysed by bioinformatic approaches. There were 650 genes significantly down-regulated and 683 genes significantly up-regulated (P<0.05) in the luteal versus follicular phase. Quantitative real-time PCR, immunoblot analysis and immunohistochemistry confirmed selected gene expression and cellular protein localization. Down-regulated genes involved macrophage recruitment, immunomodulation and matrix-degeneration, and up-regulated genes involved anti-inflammatory, ion transport, anti-angiogenic and early pregnancy recognition. The oviduct displayed some similarities and differences in progesterone-regulated genes compared with the human endometrium. Together, these data suggest a unique hormonally regulated environment during embryo development, maturation and transport through human oviduct and some conservation of progesterone signalling in tissues of common embryological origin. The oviduct serves as a conduit for spermatozoa in the peri-ovulatory phase and it nurtures and facilitates transport of the developing embryo during the luteal phase of the menstrual cycle, although precise interactions between the embryo and oviductal epithelium and secreted products are largely undefined. Herein, we investigated gene expression in human oviduct to identify candidate genes and processes that may participate in maturation and transport of the embryo as it develops implantation competence. Total RNA from human ampullary oviducts in the early luteal versus follicular phases was isolated and hybridized to oligonucleotide arrays. The data, analysed by bioinformatic approaches, revealed that 650 genes were significantly down- and 683 genes were significantly up-regulated in the luteal phase. Quantitative real-time PCR, immunoblot analysis and immunohistochemistry confirmed selected gene expression and cellular protein localization. The data demonstrated down-regulation of genes involved in macrophage recruitment, immunomodulation and matrix degeneration and up-regulation of ion transport and secretions, as well as anti-angiogenic and early pregnancy recognition. Together, these data suggest a unique hormonally regulated environment during embryo development, maturation and transport through the human oviduct and provide insight into mechanisms influencing acquisition of implantation competence of the human embryo during its passage through the oviduct en route to the uterine endometrium.


Platelet serotonin uptake: methods and strain differences.
The pharmacokinetic properties of platelets make these vascular elements a potential and convenient model for serotoninergic neurons. Because we encountered several difficulties in preliminary platelet serotonin (5HT) uptake assays, we explored the influence of several assay factors on the parameters obtained. We found that a citrate-dextrose anticoagulant stabilized platelet 5HT uptake even at room temperature. More rapid wash rates during the filtration following the assay incubation gave higher apparent uptake affinities. Platelets from an inbred strain of rats exhibited less variability in Vmax than cells from outbred strains studied. These findings, in conjunction with a human twin study also suggesting that variance in platelet 5HT uptake increases with genetic diversification, demonstrate some additional confounding factors in platelet 5HT uptake studies.


The intracellular distribution and function of the high mobility group chromosomal proteins.
This brief review provides a framework for discussing current approaches being used to determine the cellular localization and function of the high mobility group chromosomal (HMG) proteins. The four main constituents of this group (HMG 1, 2, 14, 17) are present in all four eukaryotic kingdoms, have a relatively well conserved primary sequence and contain several functional domains which enable them to interact with DNA, histones and other components of the genome. The evolutionary conservation in the primary and tertiary structure as well as the observed correlations between cell phenotype and quantitative changes in protein levels and in post-synthesis modifications suggests that these proteins are components obligatory for proper cellular function. Proteins HMG 1, 2 are DNA-binding proteins which can distinguish between various types of single-stranded regions of the genome. Proteins HMG 14, 17 may be involved in maintaining specific chromatin regions in particular conformations. The data available presently suggests that these proteins are important structural elements of chromatin and chromosomes.


Fusiform intracranial aneurysms. Clinicopathologic features.
Seven fusiform aneurysms were found at autopsy in five patients (two males and three females) over a 13-year period. The subjects were between 56 and 65 years of age. The basilar trunk was the most frequent site. Four aneurysms were of giant proportions and contained laminated thrombi. Subarachnoid hemorrhage occurred in four patients. Microscopic examination of the aneurysm walls revealed atheromatous degeneration, focal wall attenuation, mural hemorrhage, rupture, and acute and chronic inflammatory cell infiltration. These findings suggest that rupture is not rare and that atherosclerosis is but one mechanism in the pathogenesis of these lesions.


Massive air embolism as a complication of upper gastrointestinal endoscopy: A case report illustrating a stroke mimic, literature review, and suggested management.
Cerebral air embolism should be considered in case of stroke symptoms during any invasive procedure. Transport to a hospital with neurosurgical/hyperbaric oxygen treatment (HBOT) facility could improve the outcome for the patient. Absence of air on computed tomography (CT) scan should not disqualify a patient from HBOT if air embolism is suspected.


Optimization of allosteric MEK inhibitors. Part 2: Taming the sulfamide group balances compound distribution properties.
Recently, we had identified an unexplored pocket adjacent to the known binding site of allosteric MEK inhibitors which allowed us to design highly potent and in vivo efficacious novel inhibitors. We now report that our initial preclinical candidate, featuring a phenoxy side chain with a sulfamide capping group, displayed human carbonic anhydrase off-target activity and species-dependent blood cell accumulation, which prevented us from advancing this candidate further. Since this sulfamide MEK inhibitor displayed an exceptionally favorable PK profile with low brain penetration potential despite being highly oral bioavailable, we elected to keep the sulfamide capping group intact while taming its unwanted off-target activity by optimizing the structural surroundings. Introduction of a neighboring fluorine atom or installation of a methylene linker reduced hCA potency sufficiently, at the cost of MEK target potency. Switching to a higher fluorinated central core reinstated high MEK potency, leading to two new preclinical candidates with long half-lives, high bioavailabilities, low brain penetration potential and convincing efficacy in a K-Ras-mutated A549 xenograft model.


Anatomical Course of the Thyroarytenoid Branch of the Recurrent Laryngeal Nerve.
To determine the position and anatomic variability of the thyroarytenoid (TA) branch of the recurrent laryngeal nerve (RLN) in an Indian population. This study is specifically targeted to aid in identifying the nerve for reinnervation procedures for unilateral and bilateral vocal fold paralysis, as well as denervation surgeries such as TA myoneurectomy and Selective Laryngeal Adductor Denervation and Reinnervation (SLAD-R) for adductor spasmodic dysphonia. We dissected 46 fresh-frozen adult larynges (92 sides) without pathology. A window was created in the thyroid cartilage lamina. The intralaryngeal part of the dissection was done using magnification with an ocular loupe. The position and direction of the nerve and branching within the cartilage window were noted. The TA nerve was found to emerge from the posteroinferior quadrant of the cartilage window, irrespective of the dissected side (right/left) and gender in all of the 46 larynges. The nerve traveled in an oblique direction in 29 specimens (63.04%) and in a vertical direction in 17 specimens (36.96%). The orientation of the nerve was the same on the two sides of the larynx in all of the specimens. Branching was seen within the cartilage window in eight larynges (17.39%). Knowledge of the possible variabilities in the course of the TA nerve aids in its localization while avoiding trauma to the posterior branch of the RLN that innervates the posterior cricoarytenoid and is responsible for vocal fold abduction. NA Laryngoscope, 129:704-708, 2019.


A qualitative analysis of Black men's attitudes toward obesity and bariatric surgery.
Metabolic and bariatric surgery (MBS) is a safe and highly effective treatment for morbid obesity and related co-morbidities. While MBS access and insurance coverage have greatly improved, sex and racial disparities remain in utilization of MBS. To identify novel intrinsic factors that may explain Black underutilization of surgical treatments for weight management. This study was conducted in metropolitan communities of Western New York. We conducted semistructured face-to-face interviews with 27 adult Black men with a history of obesity and at least 2 obesity-related conditions (diabetes, hypertension, and/or chronic kidney disease [CKD]), about their attitudes, beliefs, behaviors, and habits related to obesity and obesity management. Interview transcripts were reviewed using thematic analysis for patterns and themes. Most participants did not perceive obesity as a serious health condition and those who had weight-loss goals did not aim for a healthy body mass index (BMI). Trust and respectful communication with physician were very important in making healthcare decisions. MBS was perceived as extreme and dangerous option for weight loss, and only participants with severe symptoms such as chronic pain were open to discussing MBS with their providers. Participants acknowledged lack of role models of similar background who had successfully undergone MBS for obesity. This study identified misinformation about risks and benefits of MBS and lack of community role models as important factors contributing to Black men's unwillingness to consider MBS. Further research is needed to facilitate patient-provider communication about weight and improve provider's ability and motivation for weight management in primary care settings.


Fluoxetine, a selective serotonin uptake inhibitor, for the treatment of outpatients with major depression.
In a double-blind, placebo-controlled study the authors found that fluoxetine, a potent and selective inhibitor of serotonin reuptake, was an effective antidepressant in moderately depressed, ambulatory outpatients. Typical adverse effects reported by patients treated with fluoxetine included agitation, nausea, fatigue, and insomnia. Compared to imipramine, fluoxetine was associated with fewer complaints of dry mouth, constipation, and dizziness.


Radiation-induced osteochondroma of the T4 vertebra causing spinal cord compression.
A case of a radiation-induced osteochondroma arising from the vertebral body of T4 in an 18-year-old man is reported. The patient presented with a history of progressive left lower extremity weakness. At 7 years of age, he had undergone resection of a cerebellar medulloblastoma and received adjunctive craniospinal irradiation and systemic chemotherapy. Both CT and MR imaging revealed an extradural mass contiguous with the posteroinferior endplate of the T4 vertebral body. This case indicates that radiation-induced osteochondroma should be considered in the differential diagnosis of patients with symptoms of myelopathy or nerve root compression and a history of radiation therapy involving the spine in childhood.


Ultrasonic characteristics of ileal tuberculosis.
Knowledge of the "pseudokidney sign" has proven beneficial in order to identify bowel lesions during ultrasound examinations. Numerous causes of the "pseudokidney sign" have been reported. Until now, however, there have been no published reports describing its association with tuberculosis. A description is given of a case of ileal tuberculosis identified by ultrasound, together with an explanation of its cause.


Evaluation of tripartite motif 59 and its diagnostic utility in benign bowel diseases and colorectal cancer.
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in developing countries. Tripartite motif-59 (TRIM59) a member of the TRIM ubiquitin ligase family, is a surface molecule that regulates biological processes such as cell proliferation, apoptosis, and tumorigenesis. Previous studies reported that TRIM59 expression was upregulated in human CRC, however, the expression pattern and role of TRIM59 in benign colorectal lesions remain unclear. Sixty patients diagnosed with CRC and 60 patients with benign lesions (Crohn's disease, ulcerative colitis, adenoma, and familial adenomatous polyposis) were recruited to the present study. TRIM59 gene expression was assessed by real-time quantitative polymerase chain reaction. Expression of TRIM59 protein and p-AKT were determined using, enzyme-linked immunoassay while p53 expression was detected by immunohistochemistry. Antioxidant/oxidant role of glutathione (GSH)/malondialdehyde (MDA) were evaluated by colorimetric methods in all of the studied groups. Our results showed upregulated expressions of TRIM59 gene and protein levels in CRC tissues and benign colonic lesions compared to nontumor tissues. Their levels were higher in inflammatory compared to noninflammatory bowel lesions. There were significant interrelations among TRIM59 gene expression, protein levels, tumor, node, metastasis staging, and the presence of metastasis (p < 0.0001). Receiver-operator characteristic curve analyses showed that at the cutoff point of 2.5 TRIM59 mRNA expression can discriminate between CRC cases and benign bowel group (area under the curve [AUC]: 0.639, sensitivity: 86.7%, specificity: 41.7%), and between CRC and controls (AUC: 0.962, sensitivity: 90%, specificity: 91.7%). TRIM59 could be a potential biomarker in the early detection, diagnosis, and treatment of benign colonic lesions and CRC.


Food-induced thermogenesis in obese children.
In 11 obese children aged 12.5 (+/- 0.7) years with normal glucose tolerance and 7 lean, control children aged 11.9 +/- 0.7 years the preload resting energy expenditure and thermogenic response to a standardised meal was measured by indirect calorimetry. Preload energy expenditure was higher in obese children when expressed in absolute terms than in controls, but was not different when corrected for lean body weight. Four children with obesity of recent onset had lower food-induced thermogenesis and insulin response then seven overweight children with long-standing obesity. Food-induced thermogenesis and insulin response showed a significant positive correlation. It is concluded that food-induced thermogenesis is reduced in the early phase of childhood obesity but increased in the later phase when hyperinsulinaemia develops, pointing towards an important role of insulin in food-induced thermogenesis.


Incidence of Inadvertent Intraoperative Hypothermia and Its Risk Factors in Patients Undergoing General Anesthesia in Beijing: A Prospective Regional Survey.
Inadvertent intraoperative hypothermia (core temperature <360 C) is a recognized risk in surgery and has adverse consequences. However, no data about this complication in China are available. Our study aimed to determine the incidence of inadvertent intraoperative hypothermia and its associated risk factors in a sample of Chinese patients. We conducted a regional cross-sectional survey in Beijing from August through December, 2013. Eight hundred thirty patients who underwent various operations under general anesthesia were randomly selected from 24 hospitals through a multistage probability sampling. Multivariate logistic regression analyses were applied to explore the risk factors of developing hypothermia. The overall incidence of intraoperative hypothermia was high, 39.9%. All patients were warmed passively with surgical sheets or cotton blankets, whereas only 10.7% of patients received active warming with space heaters or electric blankets. Pre-warmed intravenous fluid were administered to 16.9% of patients, and 34.6% of patients had irrigation of wounds with pre-warmed fluid. Active warming (OR = 0.46, 95% CI 0.26-0.81), overweight or obesity (OR = 0.39, 95% CI 0.28-0.56), high baseline core temperature before anesthesia (OR = 0.08, 95% CI 0.04-0.13), and high ambient temperature (OR = 0.89, 95% CI 0.79-0.98) were significant protective factors for hypothermia. In contrast, major-plus operations (OR = 2.00, 95% CI 1.32-3.04), duration of anesthesia (1-2 h) (OR = 3.23, 95% CI 2.19-4.78) and >2 h (OR = 3.44, 95% CI 1.90-6.22,), and intravenous un-warmed fluid (OR = 2.45, 95% CI 1.45-4.12) significantly increased the risk of hypothermia. The incidence of inadvertent intraoperative hypothermia in Beijing is high, and the rate of active warming of patients during operation is low. Concern for the development of intraoperative hypothermia should be especially high in patients undergoing major operations, requiring long periods of anesthesia, and receiving un-warmed intravenous fluids.


Screen-exposure and altered brain activation related to attention in preschool children: An EEG study.
Exposure to screens has been shown to reduce attention span in children. Increased slow-wave (theta band) and decreased fast-wave (beta and gamma bands) generated from EEG, as well as increased theta/beta ratio, have been observed in children with Attention-Deficit-Hyperactivity-Disorder (ADHD). This study examined the relationship between 6-weeks screen exposure and attention abilities in typically developing preschoolers using EEG during rest. Theta and beta bands were compared, and visual attention and parental reports for attention abilities were controlled. Results suggested that the active control group showed improved visual-attention abilities following the exposure to stories, whereas the screen group did not show improved visual attention. EEG results suggested a higher connectivity in theta vs. beta bands in the screen group, but not in the control group. Results support the negative relationship between screen exposure and attention-related patterns generated from EEG in typically developing preschool children.


Anterior and Posterior Subtalar Arthroscopy Via Anterolateral and Dorsolateral Portals.
Sinus tarsi syndrome is the clinical syndrome of lateral heel pain with local tenderness at the sinus tarsi and is frequently associated with a history of inversion sprain to the ankle. The lateral heel pain can be due to the capsule-ligamentous structures lateral to the axis of the anterior and posterior subtalar joints. Anterior and posterior subtalar arthroscopies are needed to detect and treat the disorders of both joints. In this Technical Note, we describe the details of a 2-portal arthroscopic approach to both anterior and posterior subtalar joints. This allows complete examination of all the possible sources of lateral heel pain in sinus tarsi syndrome.


Sucrose Bobs and Quinine Gapes: horse (Equus caballus) responses to taste support phylogenetic similarity in taste reactivity.
Evidence suggests that behavioural affective reactions to sweet and bitter substances are homologous in humans, nonhuman primates, and rodents. The sweet taste of sucrose elicits facial responses that include rhythmic tongue protrusions whereas the bitter taste of quinine elicits facial responses that include gapes, featuring an opening of the mouth and protrusion of the tongue. The present study using the horse (Equus caballus) was undertaken for three reasons: (1) there is debate about the presence of a sweet receptor gene in the horse, (2) there is a need to expand the examination of facial reactions to taste in lineages other than the closely related lineages of rodents and primates, and (3) the horse provides an opportunity to test the hypothesis that some social signals derive from movements related to taste reaction. The horses were given oral infusions of either sucrose or quinine and their behaviour was examined using frame-by-frame video analysis. Control groups were exposed received water or syringe insertion only. Amongst the many responses made to the infusions, the distinctive response to sucrose was a bob coupled with a slight tongue protrusion and forward movement of the ears; the distinctive response to quinine was a head extension and mouth gape accompanied by a large tongue protrusion and backward movement of the ears. Sucrose Bobs and Quinine Gapes are discussed with respect to: (1) the relevance of facial reactions to both sucrose and quinine to taste receptors in horses, (2) the similarity of features of taste expression in horses to those documented in rodents and primates, and (3) the dissimilarity between facial reactions to taste and other social signals displayed by horses.


Substrate-specific structural rearrangements of human Dicer.
Dicer has a central role in RNA-interference pathways by cleaving double-stranded RNAs (dsRNAs) to produce small regulatory RNAs. Human Dicer can process long double-stranded and hairpin precursor RNAs to yield short interfering RNAs (siRNAs) and microRNAs (miRNAs), respectively. Previous studies have shown that pre-miRNAs are cleaved more rapidly than pre-siRNAs in vitro and are the predominant natural Dicer substrates. We have used EM and single-particle analysis of Dicer-RNA complexes to gain insight into the structural basis for human Dicer's substrate preference. Our studies show that Dicer traps pre-siRNAs in a nonproductive conformation, whereas interactions of Dicer with pre-miRNAs and dsRNA-binding proteins induce structural changes in the enzyme that enable productive substrate recognition in the central catalytic channel. These findings implicate RNA structure and cofactors in determining substrate recognition and processing efficiency by human Dicer.


Müller's Muscle Conjunctival Resection Ptosis Repair in the Aesthetic Patient.
Posterior eyelid ptosis repair via the Müller's muscle-conjunctival resection procedure is an effective, reliable, and simple technique for periorbital rejuvenation in the aesthetic patient. This procedure may be performed with other periorbital rejuvenation techniques without sacrificing results. Appropriate candidates are patients with maintained levator function whose ptotic upper eyelid elevates close to a normal eyelid level upon instillation of phenylephrine drops to the superior conjunctival fornix.


Vascular anomalies in lipoid proteinosis (hyalinosis cutis et mucosae): basement membrane components and ultrastructure.
In lipoid proteinosis (LP) vascular anomalies represent severe functional defects caused by excessive deposition of basement membrane (BM)-like matrix, particularly around small subepithelial blood vessels. Correlation of microvascular anomalies in morphology and ultrastructure with extracellular matrix composition and cell interactions for elucidating vascular involvement in LP-pathophysiology. Biopsies from non-related LP-patients were analyzed by indirect immunofluorescence (IIF), electron microscopy (EM), and immune-EM (ImEM). In LP-skin and mucosa the thickened vessel walls stained strongly for the BM-components type IV collagen, laminin, perlecan, and nidogen (IIF). Integrin alpha6beta4 was regularly collocated with endothelial surface markers such as PECAM (CD31). Ultrastructure (EM) revealed highly ordered matrix deposits around microvessels, with frequently collapsed lumina, functionally compensated by increased vascular density (histology, IIF). Pericytes were trapped between these concentric BM-layers at varying distances towards the periphery (EM), contrasting their regularly close endothelial apposition. Periodic type IV collagen patterns (ImEM) corroborated the multiple BM-leaflet structure and the lack of a common 'fused' endothelial-pericyte BM, seen normally. Presumptive secretory vesicles, abundant in both cell types, implied an equal contribution to BM-synthesis, but also indicated partial loss of endothelial polarity. In LP thickened vessel walls, composed of multiple BM, profoundly alter microvascular properties, also by interference with endothelial-pericyte interactions. The increased microvascular density reflects compensatory restoration for disabled function. Most remarkable was the exaggerated secretory activity (also at luminal surfaces) underlining the regulatory key role of extracellular matrix protein 1 (ECM1; mutated in LP) in export or turnover of all major BM-components.


Polymerase chain reaction.
The PCR, like recombinant DNA technology, has had an enormous impact in both basic and diagnostic aspects of molecular biology because it can produce large amounts of a specific DNA fragment from small amounts of a complex template. Recombinant DNA techniques create molecular clones by conferring on a specific sequence the ability to replicate by inserting it into a vector and introducing the vector into a host cell. PCR represents a form of "in vitro cloning" that can generate, as well as modify, DNA fragments of defined length and sequence in a simple automated reaction. In addition to its many applications in basic molecular biological research, PCR promises to play a critical role in the identification of medically important sequences as well as an important diagnostic one in their detection.


Structural studies of virus particles.
X-ray crystallographic studies of complete virus particles have resulted in models with resolution at atomic level. They have begun to give some insight into the mechanisms behind processes in the viral life cycle such as assembly, disassembly and cell attachment.


Prevalence and prognostic relevance of myocardial inflammation and cardiotropic viruses in non-ischemic dilated cardiomyopathy.
Non-ischemic dilated cardiomyopathy (DCM) is a heterogeneous disease with a spectrum of etiological factors. However, subsets of the disease are not well-characterized with respect to these factors. The aim of this study was to evaluate the prevalence of myocardial inflammation and cardiotropic viruses in DCM patients and their impact on clinical outcome. Fifty-seven patients with DCM underwent endomyocardial biopsy between 2010 and 2013. Biopsies were analyzed by polymerase chain reaction (PCR) for the presence of cardiotropic viruses, and inflammatory cell infiltration was assessed by immunohistochemistry. During a 5-year follow-up, 27 (47%) patients reached the composite outcome measure: heart transplantation, left ventricle assist device implantation or cardiovascular-related death. Thirty-one (54%) patients had myocardial inflammation and cardiotropic viruses were detected in 29 (52%). The most frequent viruses were parvovirus B19 and human herpesvirus type-6. Four specific sub-groups were distinguished by PCR and immunohistochemistry: virus-positive (chronic) myocarditis, autoreactive inflammatory DCM, viral DCM, non-inflammatory DCM. The presence of a viral genome in myocardium or diagnosis of inflammatory DCM did not predict the outcome of composite outcome measures (p > 0.05). However, univariate Cox regression and survival function estimation revealed an association between inflammation by a high number of T-cells and poor prognosis. This study has shown that two markers - cardiotropic viruses and myocardial inflammation - are prevalent among DCM patients. They are also helpful in identifying sub-groups of DCM. An increased number of T-lymphocytes in the myocardium is a predictor of poor mid-term and long-term prognosis.


Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a] benzimidazole (TBZ).
We investigated the antitumour effects of 1-(2,6-difluorophenyl)-1H,3H-thiazolo [3,4-a]benzimidazole (TBZ) a new anti-HIV-1 agent, on human promyelocytic HL60 leukaemia, both a parental and a multidrug resistant form (HL60R). HL60R overexpresses P-glycoprotein and, like HL60, lacks p53 protein expression. HL60 and HL60R show similar levels of Bcl-2 protein. In contrast to the conventional chemotherapeutic agents daunorubicin, etoposide and mitoxantrone, TBZ caused equal or even greater cytotoxicity in HL60R than in HL60, and this result was associated with a more marked induction of apoptosis in the drug resistant cells. The antitumour activity of TBZ occurred in the range of concentrations higher than those required to exert antiviral activity. TBZ seems to act in the presence of P-glycoprotein and Bcl-2 and in the absence of p53 and is able to circumvent the mechanisms of drug resistance and anti-apoptosis present in HL60R cells.


CESAR 2.0 substantially improves speed and accuracy of comparative gene annotation.
Homology-based gene prediction is a powerful concept to annotate newly sequenced genomes. We have previously demonstrated that whole genome alignments can be utilized for accurate comparative coding gene annotation. Here we present CESAR 2.0 that utilizes genome alignments to transfer coding gene annotations from one reference to many other aligned genomes. We show that CESAR 2.0 is 77 times faster and requires 31 times less memory compared to its predecessor. CESAR 2.0 substantially improves the ability to align splice sites that have shifted over larger distances, allowing for precise identification of the exon boundaries in the aligned genome. Finally, CESAR 2.0 supports entire genes, which enables the annotation of joined exons that arose by complete intron deletions. CESAR 2.0 can readily be applied to new genome alignments to annotate coding genes in many other genomes at improved accuracy and without necessitating large-computational resources. Source code is freely available at https://github.com/hillerlab/CESAR2.0. email@example.com. Supplementary data are available at Bioinformatics online.


Oxiforms: Unique cysteine residue- and chemotype-specified chemical combinations can produce functionally-distinct proteoforms: Like how mixing primary colours creates new shades, cysteine residue- and chemotype-specified chemical combinations can produce functionally-distinct proteoforms called oxiforms: Like how mixing primary colours creates new shades, cysteine residue- and chemotype-specified chemical combinations can produce functionally-distinct proteoforms called oxiforms.
A single protein molecule with one or more cysteine residues can occupy a plurality of unique residue and oxidation-chemotype specified proteoforms that I term oxiforms. In binary reduced or oxidised terms, one molecule with three cysteines will adopt one of eight unique oxiforms. Residue-defined sulfur chemistry endows specific oxiforms with distinct functionally-relevant biophysical properties (e.g., steric effects). Their emergent complexity means a functionally-relevant effect may only manifest when multiple cysteines are oxidised. Like how mixing colours makes new shades, combining discrete redox chemistries-colours-can create a kaleidoscope of oxiform hues. The sheer diversity of oxiforms co-existing within the human body provides a biological basis for redox heterogeneity. Of evolutionary significance, oxiforms may enable individual cells to mount a broad spectrum of responses to the same stimulus. Their biological significance, however plausible, is speculative because protein-specific oxiforms remain essentially unexplored. Excitingly, pioneering new techniques can push the field into uncharted territory by quantifying oxiforms. The oxiform concept can advance our understanding of redox-regulation in health and disease.


3H-1,2,4-Dithiazol-3-one compounds as novel potential affordable antitubercular agents.
Small molecules with oxathiazol-2-one moiety were recently reported as potent inhibitors of Mycobacterium bovis var. bacilli Calmette-Guérin (BCG), among which HT1171 was the most potent and selective proteasome inhibitor. Herein we synthesized a series of novel compounds by bioisosteric replacement of the oxathiazol-2-one ring with 3H-1,2,4-dithiazol-3-one, and also fifteen 1,3,4-oxathiazol-2-one molecules in order for potency comparison and structure-activity relationship elucidation since their antibacterial effects on the virulent strains were not evaluated before. All the compounds were assessed for antitubercular activities on the virulent H37Rv strain by a serial dilution method. Among the tested compounds, 3H-1,2,4-dithiazol-3-one compound 4n was found to be the most active with a lowest MIC(90) value of 1 μg/mL. Furthermore, the cytotoxicities of all the compounds against normal human liver cell line L02 were determined by an MTT method. Compound 4n displayed a lower inhibitory ratio than HT1171 at the concentration of 100 μM, indicating its better safety profile.


Formaldehyde impairs memory, equilibrium, and dexterity in histology technicians: effects which persist for days after exposure.
Results of neurobehavioral testing in 305 histology technicians were studied by regression analysis with age, years of cigarette smoking, and hours per day of exposure to formaldehyde and to solvents as major independent variables. Increasing age was associated with poorer performance on visual memory, block design, trails, dexterity by pegboard, sharpened-Romberg, finger writing, as well as with longer choice reaction time. Increased daily hours of exposure to formaldehyde were correlated with reduced performance on story memory, visual memory, digit span, pegboard and sharpened-Romberg, as well as with errors on trails. Exposure to solvents was associated only with diminished recall of story.


Hyper-IgE syndrome caused by DOCK8 mutation with a tumour-like lesion of the lip: a case report.
Autosomal recessive hyper-IgE syndrome caused by DOCK8 gene mutation is an immunodeficiency. However, the presentation of a tumour-like lesion of the lip in autosomal recessive hyper-IgE syndrome has not yet been reported. This article reports the case of a 20-year-old man with autosomal recessive hyper-IgE syndrome who presented with a tumour-like lesion of the lip, and hyperplasia and erosion of the gingiva. The clinical manifestations included coarse face and neck skin, a diffuse tumour-like lesion on the upper lip showing a reddish erosive nodular surface with yellowish-white exudation, erosive buccal mucosa, and severe periodontitis. The swollen gingival and palatal mucosa indicated nodular hyperplasia and redness with pseudomembrane. The patient had a significantly increased peripheral blood eosinophil count and serum IgE level and an abnormal T lymphocyte count. His oral lesions improved markedly after prednisolone acetate use and local symptomatic treatment for 2 years. However, the patient unfortunately died of a cerebral infection 6 months after the oral lesions had resolved. The novel features of the labial tumour-like lesion described here extend our understanding of the manifestations of autosomal recessive hyper-IgE syndrome.


Psychosocial resources and chronic pain in individuals with spinal cord injury: evidence from the second Swiss national community survey.
Cross-sectional. To investigate the associations of a set of psychosocial resources with pain and pain-related factors in individuals with spinal cord injury (SCI) and chronic pain. Community, Switzerland. Data from 1,064 individuals with chronic pain who participated in the second community survey of the Swiss Spinal Cord Injury Cohort Study (Survey 2017) were analyzed. Multiple linear regression modeling was performed to test the hypotheses that higher levels of psychosocial resources (self-efficacy, self-esteem, purpose in life, optimism, hope, social support, sense of belonging) are negatively associated with pain intensity, pain interference and depressive symptoms. Higher self-esteem, optimism and hope were related to less pain interference and all psychosocial resources under study were negatively associated with depressive symptoms in final models. However, neither of the psychosocial resources was related to pain intensity when models were adjusted for pain interference and depressive symptoms. These findings strengthen the evidence that psychosocial resources can have an impact on pain interference and depressive symptoms as pain-related factors, and support the notion that psychosocial resources might be promising targets for pain interventions in individuals with SCI.


Involvement of opioid receptors in inhibition of bladder overactivity induced by sacral neuromodulation in pigs: A possible action mechanism.
To determine the role of opioid receptors in the inhibition of bladder overactivity by sacral neuromodulation (SNM) in pigs, and explore the possible mechanism of SNM. Both implant-driven stimulators of the S3 spinal nerve were implanted in seven pigs. Naloxone and tramadol were administered. Multiple cystometrograms were performed to determine the effects of SNM and opioid receptors on the micturition reflex by infusing normal saline (NS) or acetic acid (AA). AA-induced bladder overactivity significantly reduced the bladder capacity (BC) to 29.9 ± 3.9% of the NS control level (413.1 ± 55.4 mL) (P < 0.01). SNM significantly increased the BC to 39.4 ± 5.5% of the NS control level (P < 0.03). In the absence of SNM, the cumulative dose of naloxone (0.02 and 0.2 mg/kg intravenously) did not significantly change the BC (25.1 ± 3.1% and 20.2 ± 3.1% of the NS control level, respectively) (P > 0.05). In the presence of SNM, both doses of naloxone significantly reduced the BC to 27.2 ± 3.0% and 25.1 ± 2.9% of the NS control level (P < 0.05), respectively. In the absence of SNM, tramadol did not significantly change the BC (31.5 ± 3.9% of the NS control level) (P > 0.05). In the presence of SNM, tramadol significantly increased the BC to 49.1 ± 6.1% of the NS control level (P < 0.01). Opioid receptors play a role in inhibition of bladder overactivity during SNM. Combining SNM with tramadol could be a novel treatment modality for overactive bladder.


Genistein modulates prostate epithelial cell proliferation via estrogen- and extracellular signal-regulated kinase-dependent pathways.
Epidemiological evidence suggests that consumption of soy is associated with a decreased risk for prostate cancer. Genistein, the most abundant isoflavone present in soy, is thought to be responsible, in part, for these anticancer effects. The present study examined the effects of genistein on cellular proliferation, extracellular signal-regulated kinase (ERK1/2) activity and apoptosis in a nontumorigenic human prostate epithelial cell line (RWPE-1). Low concentrations of genistein (0-12.5 micromol/L) significantly increased cell proliferation and ERK1/2 activity (P<.01) in RWPE-1 cells, while higher concentrations (50 and 100 micromol/L) of genistein significantly inhibited cell proliferation and ERK1/2 activity (P<.001). A similar biphasic effect of genistein on MEK1 activity, an ERK1/2 kinase, was also observed. Pretreatment of cells with a MEK1 inhibitor (PD 098059) significantly blocked genistein-induced proliferation and ERK1/2 activity (P<.01). In addition, treatment of cells with ICI 182,780, a pure antiestrogen, inhibited genistein-induced RWPE-1 proliferation and ERK1/2 signaling. Taken together, these results suggest that genistein modulates RWPE-1 cell proliferation and signal transduction via an estrogen-dependent pathway involving ERK1/2 activation.


Social support in diabetes: a systematic review of controlled intervention studies.
Systematic, computerized search in Medline, the Cochrane Library, Eric, PsychINFO and Embase files, 1980-2003, selecting descriptions of prospective intervention trials with good methodological design, testing effects of social support interventions on health outcomes in primary and outpatient care for type 2 diabetes. Six controlled trials were reviewed. They defined, modified, and measured social support in various ways, and scored outcomes with varying measures. Gender differences and the right amount of support seem important. Promising new forms of social support: group consultations (better HbA1c and lifestyle), Internet or telephone-based peer support (improved perceived support, increased physical activity, respectively), and social support groups (improved knowledge and psychosocial functioning). No improved diabetes control by classic forms of support, e.g. from spouse (but weight loss in women) and family and friends (no differences). It is tentatively concluded that this review supports the hypothesis that specific social support interventions affect patient self-care and diabetes outcomes. New forms of social support may be discussed and incorporated in the work of diabetes teams, and offered to patients as new possibilities to help them adjust to a life with (type 2) diabetes and make information-based decisions. Only in the group consultations study, diabetes control was protected. More well-designed research testing the effects of specific social support interventions on patient self-care, lifestyle adaptations, and outcomes of diabetes care, is warranted.


Neural correlates of photophobia in prodromal and mild dementia with Lewy bodies.
Photophobia is a sensory disturbance provoked by light. Little is known about the association between photophobia and dementia with Lewy bodies (DLB). In this study, we aimed to identify the frequency and the neural basis of photophobia in prodromal and mild DLB. One hundred and thirteen DLB patients, 53 Alzheimer's disease (AD) patients, 20 AD and DLB patients, 31 patients with other neurocognitive diseases (including prodromal and mild demented patients), and 31 healthy elderly controls were included in this case-control study. Photophobia was systematically looked for and compared between groups. Among a selection of 77 DLB patients, we used voxel-based morphometry (VBM) to compare those with and those without photophobia (gray matter volume; SPM12, XjView, and Matlab R2021b software). The frequency of photophobia was higher in the DLB group (47.3%) than in the other groups (p = 0.002). The photophobia questionnaire score was higher in the DLB group than in the AD group (p = 0.001). Comparison between DLB patients with and those without photophobia showed decreased gray matter in the photophobia subgroup, in the right precentral cortex, in the eyelid motor region of Penfield's homunculus (p = 0.007, family-wise error [FWE] corrected). Photophobia is a quite frequent symptom of prodromal and mild DLB. The neural basis of photophobia in DLB involves the right precentral cortex, which could have a role in the decrease of cerebral excitability, but also the motricity of the eyelids.


Rational design of oral drugs targeting mucosa delivery with gut organoid platforms.
Effective oral drugs and vaccines require high delivery efficiency across the gastrointestinal epithelia and protection of medically effective payloads (i.e., immunogens) against gastric damage. In this study, hollowed nanocarriers (NCs: silica nanospheres and gold nanocages) with poly-l-lysine (PLL) coating and mammalian orthoreovirus cell attachment protein σ1 functionalization (NC-PLL-σ1) were explored as functional oral drug delivery vehicles (ODDVs). The transport of these ODDVs to mucosal lymphoid tissues could be facilitated by microfold cells (M-cells) mediated transcytosis (via σ1-α2-3-linked sialic acids adherence) across gastrointestinal epithelia. PLL coating provided protection and slow-release of rhodamine 6 G (R6G), a model payload. The transport effectiveness of these ODDVs was tested on intestinal organoid monolayers in vitro. When compared with other experimental groups, the fully functionalized ODDV system (with PLL-σ1) demonstrated two significant advantages: a significantly higher transport efficiency (198% over blank control at 48 h); and protection of payloads which led to both better transport efficiency and extended-release of payloads (61% over uncoated carriers at 48 h). In addition, it was shown that the M cell presence in intestinal organoid monolayers (modulated by Rank L stimulation) was a determining factor on the transport efficiency of the ODDVs: more M-cells (induced by higher Rank L) in the organoid monolayers led to higher transport efficiency for ODDV-delivered model payload (R6G). The fully functionalized ODDVs showed great potential as effective oral delivery vehicles for drugs and vaccines.


Preparation of samples with both hard and soft phases for electron backscatter diffraction: examples from gold mineralization.
Preparation of high-quality polished sample surfaces is an essential step in the collection of microanalytical data on the microstructures of minerals and alloys. Poorly prepared samples can yield insufficient or inconsistent results and, in the case of gold, potentially no data due to the "beilby" layer. Currently, preparation of ore samples is difficult as they commonly contain both hard and soft mineral phases. The aim of our research is to produce suitably polished sample surfaces, on all phases, for electron backscatter diffraction analysis. A combination of chemical-mechanical polishing (CMP) and broad ion-beam polishing (BIBP) was used to tackle the problem. Our results show that it is critical to perform CMP first, as it produces a suitable polish on the hard mineral phases but tends to introduce more damage to the soft mineral surfaces. BIBP is essential to produce a high-quality polish to the soft phases (gold). This is a highly efficient method of sample preparation and is important as it allows the complete quantification of ore textures and all constituent mineral phases, including soft alloys.


Visual receptive fields of units in the pulvinar of cebus monkey.
Visually driven units, isolated in the ventrolateral group -- Pv1g (109) and in subnucleus Pmu (33) of the pulvinar of the cebus monkey, were studied in acute and chronic preparations under nitrous oxide N2O/O2 anesthesia during periods of EEG arousal. Taking into consideration the response properties to static or moving stimuli as well as the organization of the receptive fields, units isolated in the pulvinar were subdivided into 8 groups. Units displaying dynamic properties predominate over static ones. Static units were classified in 3 groups; of these, one showed uniform receptive fields; the remaining two groups, with non-uniform RFs, were further subdivided in terms of orientation selectivity. By testing for directional sensitivity, organization of the RFs and orientation selectivity, the dynamic units were divided in 5 groups. Among these there was a predominance of directional units, displaying uniform RFs and showing orientation selectivity. Although the receptive fields would extend into the ipsilateral hemifield (up to 10 degrees), their centers were always located in the contralateral visual hemifield. Binocularly driven units predominate in both static and dynamic categories.


An alternative grading system to refine the criteria for severity of hydronephrosis and optimal treatment guidelines in neonates with primary UPJ-type hydronephrosis.
We present our alternative hydronephrosis grading system (AGS) in an attempt to establish optimal treatment guidelines, and clarify and refine the criteria for severity of hydronephrosis in neonates. A total of 162 newborns (228 affected kidneys) with antenatally diagnosed primary ureteropelvic junction-type hydronephrosis were prospectively followed and treated by the same surgeon for a mean of 46 (6-65) months. Ultrasonography and diuretic renogram were used for diagnosis and follow up. Society for Fetal Urology (SFU) grading system, anteroposterior diameter of renal pelvis (APDRP) and our AGS were used to determine the degree of hydronephrosis. AGS: 0, no hydronephrosis; 1, dilatation of renal pelvis alone; 2, plus caliceal dilatation; 3, plus <1/2 (mild-to-moderate) renal parenchymal loss; 4, plus >1/2 (severe) renal parenchymal loss (cyst-like kidney with no visually significant renal parenchyma). On the first postnatal ultrasound, the severity of hydronephrosis was SFU< or =2 in 152 kidneys (surgery, 0%), SFU-3 in 41 kidneys (surgery, 19.5%) and SFU-4 in 35 kidneys (surgery, 68.6%). The follow up, treatment and outcome of SFU-1 and SFU-2 patients were similar; all resolved spontaneously without renal deterioration (renal function >40%). Renal function ranged between 7% and 39% in SFU-4 patients. Intrarenal pelvis was found in one patient with an APDRP of <15 mm, seven patients of 16-30 mm, and five patients of >30 mm. Overall, 201 hydronephrotic kidneys (88.2%) resolved spontaneously while 27 (11.8%) required pyeloplasty. Neither an SFU grading system nor measurement of APDRP is the gold standard in determining the severity of hydronephrosis. Both methods may fail, particularly in children with intrarenal pelvis configuration or SFU-4 hydronephrosis. Our AGS promises easier follow up and more timely treatment.


Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein-Protein Interaction.
The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein-protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.


Low-pressure hydrogenation of carbon dioxide catalyzed by an iron pincer complex exhibiting noble metal activity.
A highly active iron catalyst for the hydrogenation of carbon dioxide and bicarbonates works under remarkably low pressures and achieves activities similar to some of the best noble metal catalysts. A mechanism is proposed involving the direct attack of an iron trans-dihydride on carbon dioxide, followed by ligand exchange and dihydrogen coordination.


Laparoscopic central pancreatectomy: single institution experience of 6 patients.
Medial pancreatectomy is an alternative technique for benign or low-grade malignant tumors of the neck of the pancreas. We describe our experience of laparoscopic central pancreatectomy. We conducted a prospective evaluation of laparoscopic pancreatic resection in the Department of Abdominal Surgery at Haut-Lévêque Hospital, CHU Bordeaux. From January 1999 until February 2006, 397 patients underwent pancreatic resection for pancreatic lesions, of whom 60 (15%) were enrolled for laparoscopic pancreatic resection. Of the 60 patients, 6 underwent laparoscopic central pancreatectomy. Surgical procedure, postoperative course, and follow-up data were collected. Laparoscopic central pancreatectomy was successful in all patients. In 1 case, we had to perform a laparotomy to find the specimen, which had been lost in the cavity during the anastomosis. The median operative time was 225 minutes (range, 180 to 365 minutes). None of the patients required blood transfusion in the perioperative period, and there was no mortality. Symptomatic pancreatic fistula occurred in 2 patients (33%). None of the patients required reoperation or radiologic drainage. Oral feeding was resumed in a median of 11 days (range, 9 to 21 days). The median postoperative hospital stay was 18 days (range, 15 to 25 days). At a median follow-up of 15 months (range, 4 to 34 months), all patients were alive without exocrine or endocrine insufficiency. Laparoscopic central pancreatectomy is feasible and safe. Laparoscopic central pancreatectomy may become the standard approach for resection of benign or low-grade malignant tumors of the neck of the pancreas if performed by highly skilled surgeons.


Facile synthesis of active antitubercular, cytotoxic and antibacterial agents: a Michael addition approach.
Spiro derivatives of oxindole and isoxazole-5-one were synthesized by using Michael addition reaction, highlighting the regioselective approach towards the synthesis of Michael diadduct followed by condensation of Michael diadduct. The spiro compound 4 showed antitubercular activity against Mycobacterium tuberculosis H37Rv whereas spiro compound 9 possesses pronounced anticancer and antibacterial profile.


Replacement of the systemic atrioventricular valve with a mechanical prosthesis in children aged less than 6 years: late clinical results of survival and subsequent replacement.
We analyzed the survival, clinical course, and role of prosthesis-patient mismatch after systemic atrioventricular valve replacement in children. From 1974 to 2006, 69 patients underwent systemic atrioventricular valve replacement (median age 1.2 years, range 1.1 months to 5.4 years), with 17 patients requiring re-replacement of the systemic atrioventricular valve. Prosthesis-patient relationship was analyzed by comparing (1) the prosthetic valve diameter and the predicted annulus diameter based on the body surface area and (2) the prosthetic valve diameter and the measured annulus diameter. Survival was 73% at 1 year and 65% at 5, 10, and 15 years. Age, weight, body surface area, predicted annulus diameter, prior surgery, underlying disease, and ratio of prosthetic valve diameter to body weight were significant predictors of death. Variables associated with re-replacement of the systemic atrioventricular valve were body surface area, prosthetic valve diameter, predicted annulus diameter, and presence of multiple left-sided obstructive lesions. The majority of patients received a prosthesis larger than the predicted annulus diameter. There was good correlation between the prosthetic valve diameter and the measured annulus diameter (r = 0.85). Mismatch, as described by the difference in z scores of prosthetic valve diameter and measured annulus diameter, was not a significant predictor of death or re-replacement of the systemic atrioventricular valve. Although valve replacement is considered the last therapeutic option after failed attempts of valvuloplasty, long-term outcome is favorable. Selection of the prosthesis is made on the basis of the measured annulus diameter. An elevated ratio of prosthetic valve diameter to body weight is associated with patients with low body weight or a large native annulus in dilated ventricles.


BMPMDA: Prediction of MiRNA-Disease Associations Using a Space Projection Model Based on Block Matrix.
With the high-quality development of bioinformatics technology, miRNA-disease associations (MDAs) are gradually being uncovered. At present, convenient and efficient prediction methods, which solve the problem of resource-consuming in traditional wet experiments, need to be further put forward. In this study, a space projection model based on block matrix is presented for predicting MDAs (BMPMDA). Specifically, two block matrices are first composed of the known association matrix and similarity to increase comprehensiveness. For the integrity of information in the heterogeneous network, matrix completion (MC) is utilized to mine potential MDAs. Considering the neighborhood information of data points, linear neighborhood similarity (LNS) is regarded as a measure of similarity. Next, LNS is projected onto the corresponding completed association matrix to derive the projection score. Finally, the AUC and AUPR values for BMPMDA reach 0.9691 and 0.6231, respectively. Additionally, the majority of novel MDAs in three disease cases are identified in existing databases and literature. It suggests that BMPMDA can serve as a reliable prediction model for biological research.


Evaluation of seven PCR-based assays for the analysis of microchimerism.
The presence of small numbers of cells of donor origin in the circulation of recipients of organ transplants (microchimerism) may correlate with immunologic tolerance. As part of our ongoing studies on microchimerism, we evaluated the utility of seven PCR-based assays for the detection of the less abundant DNA in paired mixtures (100 ng total DNA). DNA samples were screened to identify pairs informative for one or more PCR assays. DNA mixtures from the informative pairs were then analyzed using at least one assay. The assays were based on the X-Y homologous region; a Y chromosome microsatellite locus; three autosomal microsatellite loci; the D1S80 minisatellite locus; and sequence specific oligonucleotide probe (SSOP) analysis of the HLA DRB1 locus. About 0.1% of male DNA against a background of female DNA was detectable using primers for the X-Y homologous region, but the sensitivity was increased to 0.0001% using nested primers for the Y chromosome microsatellite marker. Analysis of the minor DNA component was difficult with the three autosomal microsatellite assays because of the presence of shadow bands. Similar problems with the D1S80 assay were resolved using more stringent PCR conditions, and the sensitivity was 0.1%. Using the DRB1 locus, we were able to detect 1% DNA in the mixed samples. These studies show that: (a) nested PCR for the Y chromosome is the most sensitive assay for the detection of microchimerism; (b) D1S80 is a useful marker for microchimerism; (c) additional optimization of analytical conditions is required if autosomal microsatellite markers and the SSOP assay are to be used for microchimerism analysis.


Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins.
Neuropilin-1 and neuropilin-2 show specificity in binding to different class III semaphorins, including Sema III, Sema E, and Sema IV, suggesting that the specificity of action of these semaphorins is dictated by the complement of neuropilins expressed by responsive neurons. In support of this, we show that sympathetic axons coexpress neuropilin-1 and -2, that their responses to Sema III, Sema E, and Sema IV are affected in predicted ways by antibodies to neuropilin-1, and that neuropilin-1 and -2 can form homo- and heterooligomers through an interaction involving at least partly the neuropilin MAM (meprin, A5, mu) domain. These results support the idea that in sympathetic axons, the Sema III signal is mediated predominantly by neuropilin-1 oligomers, the Sema IV signal by neuropilin-2 oligomers, and the Sema E signal by neuropilin-1 and -2, either as homo- or heterooligomers.


Physical activity and all-cause mortality among older Brazilian adults: 11-year follow-up of the Bambuí Health and Aging Study.
To investigate the association between physical activity (eg, energy expenditure) and survival over 11 years of follow-up in a large representative community sample of older Brazilian adults with a low level of education. Furthermore, we assessed sex as a potential effect modifier of this association. A population-based prospective cohort study was conducted on all the ≥60-year-old residents in Bambuí city (Brazil). A total of 1,606 subjects (92.2% of the population) enrolled, and 1,378 (85.8%) were included in this study. Type, frequency, and duration of physical activity were assessed in the baseline survey questionnaire, and the metabolic equivalent task tertiles were estimated. The follow-up time was 11 years (1997-2007), and the end point was mortality. Deaths were reported by next of kin during the annual follow-up interview and ascertained through the Brazilian System of Information on Mortality, Brazilian Ministry of Health. Hazard ratios (95% confidence intervals [CIs]) were estimated by Cox proportional-hazard models, and potential confounders were considered. A statistically significant interaction (P<0.03) was found between sex and energy expenditure. Among older men, increases in levels of physical activity were associated with reduced mortality risk. The hazard ratios were 0.59 (95% CI 0.43-0.81) and 0.47 (95% CI 0.34-0.66) for the second and third tertiles, respectively. Among older women, there was no significant association between physical activity and mortality. It was possible to observe the effect of physical activity in reducing mortality risk, and there was a significant interaction between sex and energy expenditure, which should be considered in the analysis of this association in different populations.


Increasing prevalence of primary biliary cholangitis in Victoria, Australia.
The prevalence of primary biliary cholangitis (PBC) reported in different countries varies significantly and in some parts of the world appears to be increasing. The aim of this study was to determine the 2013 prevalence of PBC in Victoria, Australia, and to determine the time trend by comparing it with previous studies undertaken in 1991 and 2002. Four case-finding methods were used to identify cases of PBC in Victoria: (1) physicians' survey; (2) tertiary hospital search; (3) liver transplant database search; and (4) private pathology antimitochondrial antibody search. The prevalence of PBC in Victoria, Australia, is 189.0 per million using all four methods. The average annual increase in prevalence from 1991 to 2013 was 7.7 per million per year. Using the same case-finding methods as the 1991 Victorian prevalence study (methods 1 and 2), the prevalence of PBC increased from 19.1 per million in 1991 to 49.4 per million in 2002 (P < 0.001) and to 80.7 per million in 2013 (P < 0.001). The current prevalence of PBC in Victoria is significantly higher than previously reported. The use of private pathology-based case-finding methods is important in identifying the maximum number of PBC cases.


Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist.
The discovery, in vitro and in vivo studies of the highly potent ETA antagonist EMD 122946 are presented. This compound displayed high binding affinity and functional antagonism [IC50 = 3.2 x 10(-11) M, pA2 = 9.5 (ETA)] and inhibited the ET-1 induced pressor response in pithed rats with an ED50 of 0.3 mg/kg. In conscious spontaneously hypertensive rats and in DOCA-salt hypertensive rats the compound lowered mean blood pressure with an ED50 of 0.06 mg/kg. EMD 122946 exhibited high bioavailability in rats and monkeys.


Mechanism of bisphenol S exposure on color sensitivity of zebrafish larvae.
Color vision, initiated from cone cells, is vitally essential for identifying environmental information in vertebrate. Although the retinotoxicity of bisphenol S (BPS) has been reported, data on the influence of BPS treatment on cone cells are scarce. In the present study, transgenic zebrafish (Danio rerio) labeling red and ultraviolet (UV) cones were exposed to BPS (0, 1, 10, and 100 μg/L) during the early stages of retinal development, to elucidate the mechanism underlying its retinal cone toxicity of BPS. The results showed that 10 and 100 μg/L BPS induced oxidative DNA damage, structural damage (decreased number of ribbon synapses), mosaic patterning disorder, and altered expression of genes involved in the phototransduction pathway in red and UV cones. Furthermore, BPS exposure also caused abnormal development of key neurons (retinal ganglion cells, optic nerve, and hypothalamus), responsible for transmitting the light-electrical signal to brain, and thereby resulted in inhibition of light-electrical signal transduction, finally diminishing the spectral sensitivity of zebrafish larvae to long- and short-type light signal at 5 day post fertilization. This study highlights the cone-toxicity of environmental relevant concentrations of BPS, and clarifies the mechanism of color vision impairment induced by BPS at the cellular level, updating the understanding of visual behavior driven by environmental factors.


Improving mortality following emergent surgery in older patients requires focus on complication rescue.
To determine whether a hospital's ability to rescue patients from major complications underlies variation in outcomes for elderly patients undergoing emergent surgery. Perioperative mortality rates in elderly patients undergoing emergent general/vascular operations are high and vary widely across Michigan hospitals. We identified 23,224 patients undergoing emergent general/vascular surgical procedures at 41 hospitals within the Michigan Surgical Quality Collaborative between 2006 and 2011. Hospitals were ranked by risk- and reliability-adjusted 30-day mortality rates and grouped into tertiles. We stratified patients by age (<75 and ≥75 years). Risk-adjusted major complication and failure-to-rescue (ie, mortality after major complication) rates were determined for each tertile of hospital mortality. Risk-adjusted mortality rates in elderly patients varied 2-fold across all hospitals. Complication rates correlated poorly with mortality. Failure-to-rescue rates, however, were markedly higher in high-mortality hospitals (29% lowest tertile vs 41% highest tertile; P < 0.01). When compared with younger patients, overall failure-to-rescue rates were almost 2-fold greater in the elderly (36.1% ≥75 vs 18.7% <75; P < 0.01). A hospital's failure to rescue patients from major complications seems to underlie the variation in mortality rates across Michigan hospitals after emergent surgery. Although higher failure-to-rescue rates in the elderly may signify their diminished physiological reserve for surviving critical illness, the wide variation across hospitals also highlights the importance of systems aimed at the early recognition and effective management of major complications in this vulnerable population.


Role of follicle-stimulating hormone on biliary cyst growth in autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by the progressive development of renal and hepatic cysts. Follicle-stimulating hormone (FSH) has been demonstrated to be a trophic factor for biliary cells in normal rats and experimental cholestasis induced by bile duct ligation (BDL). To assess the effect of FSH on cholangiocyte proliferation during ADPKD using both in vivo and in vitro models. Evaluation of FSH receptor (FSHR), FSH, phospho-extracellular-regulated kinase (pERK) and c-myc expression in liver fragments from normal patients and patients with ADPKD. In vitro, we studied proliferating cell nuclear antigen (PCNA) and cAMP levels in a human immortalized, non-malignant cholangiocyte cell line (H69) and in an immortalized cell line obtained from the epithelium lining the hepatic cysts from the patients with ADPKD (LCDE) with or without transient silencing of the FSH gene. Follicle-stimulating hormone is linked to the active proliferation of the cystic wall and to the localization of p-ERK and c-myc. This hormone sustains the biliary growth by activation of the cAMP/ERK signalling pathway. These results showed that FSH has an important function in cystic growth acting on the cAMP pathway, demonstrating that it provides a target for medical therapy of hepatic cysts during ADPKD.


High-affinity receptors for interleukin-2 are not required for the induction of human unstimulated B lymphocyte differentiation by this lymphokine.
We have reported that one of the currently known receptors for interleukin-2 (IL-2), the p70 protein, is constitutively expressed on resting T lymphocyte membrane. We demonstrated that exposure of these cells to high concentrations of IL-2 resulted in the transcription of genes whose expression occurred early during cell activation such as cmyc, cmyb protooncogenes, and the Tac gene itself. IL-2 is thought to exert its biological effects by binding to its high-affinity receptors on cell membrane. Recent studies using B cell lines emphasized that within the high-affinity receptor complexes, p55 serves to allow high-affinity binding, and p70, to transduce signals. In this study, we prepared human unstimulated B cells devoid of detectable Tac antigen, and consequently, of the high-affinity receptor complexes. We designed experiments such that no in vitro de novo expressed receptors, if any, could interact with IL-2, so that any biologic events triggered by IL-2 must have been mediated in the absence of the high-affinity receptors. Under these conditions, we demonstrated that a short and unique exposure (1 hr) of these cells to high concentrations (5 nM) of IL-2 allowed its binding to cell membrane and resulted in a competent signal leading to the generation of a majority of 25S Tac mRNA, and a progression signal allowing B cell terminal differentiation into plasma cells.


Pubococcygeal repair ad modum Ingelman-Sundberg. A retrospective investigation with 10-20 years time of observation.
Fifty-one women operated on for stress incontinence with pubococcygeal repair ad modum Ingelman-Sundberg between 1955 and 1965 were investigated urogynecologically. The time of observation was accordingly at least 10 years in every case. An evaluation was made of this operation method, the distribution of recurrences during the postoperative period and possible side effects. Eight women had symptoms of at least degree I stress incontinence and thirteen showed signs of incontinence at the examination. Only four had both symptoms and signs of incontitinence. The cure rate from a symptomatic point of view was 84% and from the technical aspect 75%. Most fo the severe recurrences occurred in the first postoperative year. Thereafter the recurrences were evenly distributed. The only side effect in the long run was a tendency to rectocele.


Cross talk between intracellular pathogens and cell death.
Infections with bacterial pathogens often results in the initiation of programmed cell death as part of the host innate immune defense, or as a bacterial virulence strategy. Induction of host cell death is controlled by an elaborate network of innate immune and cell death signaling pathways and manifests in different morphologically and functionally distinct forms of death, such as apoptosis, necroptosis, NETosis and pyroptosis. The mechanism by which host cell death restricts bacterial replication is highly cell-type and context depended, but its physiological importance is highlighted the diversity of strategies bacterial pathogens use to avoid induction of cell death or to block cell death signaling pathways. In this review, we discuss the latest insights into how bacterial pathogens elicit and manipulate cell death signaling, how different forms of cell death kill or restrict bacteria and how cell death and innate immune pathway cross talk to guard against pathogen-induced inhibition of host cell death.


Shelter-Building Insects and Their Role as Ecosystem Engineers.
Amelioration of harsh conditions, manipulation of host plant quality, and protection from natural enemies have all been suggested as potential forces in the evolution and maintenance of concealed feeding in insects. The construction of shelters--either in the form of mines, galls, and leaf rolls--are expected to increase larval survivorship and might influence other organisms of the community through non-trophic direct and indirect effects when shelters are co-occupied or occupied after abandonment, placing leaf and stem shelter-builders within the context of ecosystem engineering. In this review, we evaluate the potential of shelter built by insects to reduce pressure exerted by natural enemies, increase tissue quality, and provide shelter against abiotic conditions experienced during insect development. Through a quantitative analysis, we also examined the effects of insect shelters on patterns of richness and abundance of local communities, reviewing the data published in the last 15 years. We demonstrate strong effects of shelters on several arthropods, with increased richness and abundance when shelters are present in the host plants. These results reinforce the importance of the physical structures created by insects that although subtle, might have important roles in facilitative interactions.


The G51D SNCA mutation generates a slowly progressive α-synuclein strain in early-onset Parkinson's disease.
Unique strains of α-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial α-synuclein inclusions, α-synuclein aggregates in Parkinson's disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding α-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD α-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced α-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing α-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of α-synuclein aggregates in restricted regions of the brain. The induced α-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating α-synuclein strain that more closely resembles α-synuclein aggregates associated with PD than MSA.


Compliance of Interventional Radiologists With Interventional Oncology Accreditation Standards.
We aimed to evaluate interventional radiologists' compliance with patient care and the quality management process of cancer patients using a national survey. An electronic survey was designed with questions derived from the core criteria of the International Accreditation System for Interventional Oncology (IASIOS), with the approval of the IASIOS council. Among the interventional radiologists contacted by e-mail through the national association, 34 responded to the questionnaire. The agreement of the participants with the core requirements was evaluated in five questions consisting of 34 articles using the 5-point Likert scale. Regarding the years of experience in interventional radiology (IR), the mean scale for the less than five-year group was 118.4, while that for the group with more than 15 years was 145.17 (p = 0.030). The mean scale of the five- to 15-year-old group was 121.75, versus that of more than 15 years, which was 145.17 (p = 0.028). Thus, significant differences arose between <five years versus >15 years and five to 15 years versus >15 years groups; later groups were more likely to comply. There was also a statistical difference between the groups formed according to the ratio of oncological interventions (<25% vs. 25%-50%) in the daily workload (p = 0.010). Increased experience in IR and more relay on oncological interventions appear to augment compliance with the IASIOS criteria. We believe that interventional radiologists who have distinct territorial praxis could benefit from such a framework with improved self-awareness.


Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis.
Even in the tyrosine kinase inhibitors era, the prognosis of patients with chronic myeloid leukaemia in myeloid blast crisis remains dismal with few patients surviving longer than 6 months. Here we report the cases of 5 patients treated with the combination of 5-azacytidine and tyrosine kinase inhibitors for myeloid blast crisis CML. All patients achieved a complete haematological response including two with a complete cytogenetic and major molecular response. Two patients underwent an allogeneic stem cell transplantation. One died from relapse 34 months from diagnosis. The second is alive and free from disease at 11 months from diagnosis. The other 3 patients are still in complete haematological response after 15, 24 and 33 months of follow-up. These results suggest that the combination has a significant activity in myeloid blast crisis and may increase survival.


Hedgehog signaling underlying tendon and enthesis development and pathology.
Hedgehog (Hh) signaling has been widely acknowledged to play essential roles in many developmental processes, including endochondral ossification and growth plate maintenance. Furthermore, a rising number of studies have shown that Hh signaling is necessary for tendon enthesis development. Specifically, the well-tuned regulation of Hh signaling during development drives the formation of a mineral gradient across the tendon enthesis fibrocartilage. However, aberrant Hh signaling can also lead to pathologic heterotopic ossification in tendon or osteophyte formation at the enthesis. Therefore, the therapeutic potential of Hh signaling modulation for treating tendon and enthesis diseases remains uncertain. For example, increased Hh signaling may enhance tendon-to-bone healing by promoting the formation of mineralized fibrocartilage at the healing interface, but pathologic heterotopic ossification may also be triggered in the adjacent tendon. Further work is needed to elucidate the distinct functions of Hh signaling in the tendon and enthesis to support the development of therapies that target the pathway.