Environmental effects on the enhancement in natural and damaged DNA nucleobase acidity because of discrete hydrogen-bonding interactions.
The present study uses density functional theory to carefully consider the effects of the environment on the enhancement in (natural and damaged) DNA nucleobase acidities because of multiple hydrogen-bonding interactions. Although interactions with one small molecule can increase the acidity of the nucleobases by up to 60 kJ mol-1 in the gas phase, the maximum increase in enzymatic-like environments is expected to be approximately 40 kJ mol-1, which reduces to approximately 30 kJ mol-1 in water. Furthermore, the calculated (simultaneous) effects of two, three, or four molecules are increasingly less than the sum of the individual (additive) effects with an increase in the number and acidity of the small molecules bound or the dielectric constant of the solvent. Regardless of these trends, our calculations reveal that additional hydrogen-bonding interactions will have a significant effect on nucleobase acidity in a variety of environments, where the exact magnitude of the effect depends on the properties of the small molecule bound, the nucleobase binding site, and the solvent. The maximum increase in nucleobase acidity because of interactions with up to four small molecules is approximately 80 kJ mol-1 in enzymatic-like environments (or 65 kJ mol-1 in water). These results suggest that hydrogen-bonding interactions likely play an important role in many biological processes by changing the physical and chemical properties of the nucleobases.


Dravet Syndrome: A Sodium Channel Interneuronopathy.
Dravet Syndrome is a devastating childhood epilepsy disorder with high incidence of premature death plus comorbidities of ataxia, circadian rhythm disorder, impaired sleep quality, autistic-like social-interaction deficits and severe cognitive impairment. It is primarily caused by heterozygous loss-of-function mutations in the SCN1A gene that encodes brain voltage-gated sodium channel type-1, termed NaV1.1. Here I review experiments on mouse genetic models that implicate specific loss of sodium currents and action potential firing in GABAergic inhibitory interneurons as the fundamental cause of Dravet Syndrome. The resulting imbalance of excitatory to inhibitory neurotransmission in neural circuits causes both epilepsy and co-morbidities. Promising therapeutic approaches involving atypical sodium channel blockers, novel drug combinations, and cannabidiol give hope for improved outcomes for Dravet Syndrome patients.


Conductive Microgel Annealed Scaffolds Enhance Myogenic Potential of Myoblastic Cells.
Bioelectricity is an understudied phenomenon to guide tissue homeostasis and regeneration. Conductive biomaterials may capture native or exogenous bioelectric signaling, but incorporation of conductive moieties is limited by cytotoxicity, poor injectability, or insufficient stimulation. Microgel annealed scaffolds are promising as hydrogel-based materials due to their inherent void space that facilitates cell migration and proliferation better than nanoporous bulk hydrogels. We generated conductive microgels from poly(ethylene) glycol and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) to explore the interplay of void volume and conductivity on myogenic differentiation. PEDOT:PSS increased microgel conductivity over 2-fold while maintaining stiffness, annealing strength, and viability of associated myoblastic cells. C2C12 myoblasts exhibited increases in the late-stage differentiation marker myosin heavy chain as a function of both porosity and conductivity. Myogenin, an earlier marker, was influenced only by porosity. Human skeletal muscle derived cells exhibited increased Myod1, IGF-1, and IGFBP-2 at earlier time points on conductive microgel scaffolds compared to non-conductive scaffolds. They also secreted higher levels of VEGF at early time points and expressed factors that led to macrophage polarization patterns observed during muscle repair. These data indicate that conductivity aids myogenic differentiation of myogenic cell lines and primary cells, motivating the need for future translational studies to promote muscle repair. This article is protected by copyright. All rights reserved.


Validity of women's self-reports of cancer screening test utilization in a managed care population.
This study was undertaken to examine the validity of self-reported data on breast and cervical cancer screening behavior. An abbreviated version of the Behavioral Risk Factor Surveillance System telephone survey, including questions on mammography, clinical breast examination (CBE), and Papanicolaou test utilization, was administered to a sample of 480 women aged 40-74 years, enrolled in Kaiser Permanente Colorado for at least 5 years. Screening information reported in the telephone interview was compared with that abstracted from respondents' medical records. The vast majority of women had a mammogram, CBE, and Pap test according to both self-report and medical record. Sensitivity for determining whether her last test was within 2 years (3 years for Pap test) exceeded 95% for all, whereas specificities were <55%. The percentage of overall agreement between self-reported and recorded information was 88.4% (kappa = 0.62) for mammography, 87.9% (kappa = 0.45) for CBE, and 87.2% (kappa = 0.54) for Pap test. Pearson correlations between self-reported and recorded information for specific time interval since most recent mammogram, CBE, and Pap test were 0.72, 0.58, and 0.65, respectively. Correlation increased greatly when time interval was allowed to vary by +/-1 year. In most cases of disagreement, the self-report underestimated the time since last screening. These results suggest that self-reporting of breast and cervical cancer screening is fairly accurate in this managed care population, although women tend to underestimate the time since their last screening.


Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.
Tumor necrosis factor-alpha (TNF) is implicated in the initiation of neuropathic pain. In vitro, TNF activates p38 mitogen-activated kinase. Accordingly, we investigated whether TNF activates the p38 cascade in vivo to trigger pain behavior after spinal nerve ligation (SNL). Treatment starting 2 d before SNL with the TNF antagonist etanercept (1 mg, i.p., every third day) attenuated mechanical allodynia. Treatment starting 1 or 7 d after SNL was ineffective. Similarly, intrathecal infusion of a p38 inhibitor (SB203580, 4 mg/d) was effective only if it was started before but not 7 d after SNL. For both treatments, the cessation of therapy resulted in increased allodynia. In separate experiments using Western blots and immunohistochemistry, ipsilateral lumbar spinal cord and L5 and L6 DRG were analyzed for total and phosphorylated p38 after SNL alone or SNL combined with etanercept pretreatment. In DRG, activated p38 was transiently elevated 5 hr after SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38 was activated between 5 hr and 3 d after SNL and returned to baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL treatment, phosphorylated p38 levels in spinal cord and DRG are transiently elevated. In DRG, p38 activation is blocked by systemic TNF inhibition. Parallel inhibition of p38 activation and allodynia may represent a clinically relevant therapeutic window. These data suggest a sequential role for TNF and p38 in the induction of neuropathic pain.


MDM2 is a useful prognostic biomarker for resectable gastric cancer.
Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.


Localization of mitochondrial DNA encoded cytochrome c oxidase subunits I and II in rat pancreatic zymogen granules and pituitary growth hormone granules.
Cytochrome c oxidase (COX) complex is an integral part of the electron transport chain. Three subunits of this complex (COX I, COX II and COX III) are encoded by mitochondrial (mit-) DNA. High-resolution immunogold electron microscopy has been used to study the subcellular localization of COX I and COX II in rat tissue sections, embedded in LR Gold resin, using monoclonal antibodies for these proteins. Immunofluorescence labeling of BS-C-1 monkey kidney cells with these antibodies showed characteristic mitochondrial labeling. In immunogold labeling studies, the COX I and COX II antibodies showed strong and specific mitochondrial labeling in the liver, kidney, heart and pancreas. However, in rat pancreatic acinar tissue, in addition to mitochondrial labeling, strong and specific labeling was also observed in the zymogen granules (ZGs). In the anterior pituitary, strong labeling with these antibodies was seen in the growth hormone secretory granules. In contrast to these compartments, the COX I or COX II antibodies showed only minimal labeling (five- to tenfold lower) of the cytoplasm, endoplasmic reticulum and the nucleus. Strong labeling with the COX I or COX II antibodies was also observed in highly purified ZGs from bovine pancreas. The observed labeling, in all cases, was completely abolished upon omission of the primary antibodies. These results provide evidence that, similar to a number of other recently studied mit-proteins, COX I and COX II are also present outside the mitochondria. The presence of mit-DNA encoded COX I and COX II in extramitochondrial compartments, provides strong evidence that proteins can exit, or are exported, from the mitochondria. Although the mechanisms responsible for protein exit/export remain to be elucidated, these results raise fundamental questions concerning the roles of mitochondria and mitochondrial proteins in diverse cellular processes in different compartments.


Regiocontrolled palladium-catalyzed and copper-mediated C-H bond functionalization of protected L-histidine.
We describe the controlled and regioselective transition-metal-catalyzed C-H bond arylation of protected L-histidine with aryl halides as the coupling partner. Using this approach, a large number of C-2 arylated L-histidines have been synthesized with diverse substitutions bearing electron-donating and electron-withdrawing groups, in good to excellent yields. These synthetic amino acids possessing dual hydrophobic-hydrophilic character are important synthons of bioactive peptidomimetics, which are imperative potent inhibitors of Cryptococcus neoformans.


Evaluation of the Amor and ESSG classification criteria for spondylarthropathies in a Turkish population.
This study evaluated the Amor and European Spondylarthropathy Study Group (ESSG) classification criteria for spondyloarthropathies in Turkish patients seen from October 1990 to August 1993 at the Physical Medicine and Rehabilitation Department of the GATA Haydarpasa Training Hospital. The Amor and ESSG criteria were evaluated in 157 patients with spondylarthropathies and in 124 controls with a variety of other rheumatic diseases. The sensitivity, specificity, positive predictive value, and negative predictive value of each criteria set were calculated, as well as the sensitivity and specificity of each of the 24 criteria used in these sets. For Amor's criteria, sensitivity was 88.5%, specificity was 91.9%, positive predictive value was 93.3% and negative predictive value was 86.4%. For the ESSG criteria, sensitivity was 86.6%, specificity was 91.1%, positive predictive value was 92.5% and negative predictive value was 84.3%. No significant differences were found between the two criteria sets. Our data show that the Amor and ESSG criteria are of similar value for the classification of spondylarthropathies and are comparable in terms of sensitivity and specificity. They also demonstrate the need for monitoring patients with equivocal clinical patterns using both sets of criteria as tools that complement each other.


Cisplatin plus gemcitabine for treatment of breast cancer patients with brain metastases; a preferential option for triple negative patients?
To assess the efficacy and tolerability of Cisplatin plus Gemcitabine combination in patients with brain metastases (BM) from breast cancer (BC). Eighteen BC patients with BM who were treated with Cisplatin plus Gemcitabine regimen between 2003-2011 were evaluated. A median of 6 cycles of this regimen were received, in fifteen patients (83.3%) as first-line chemotherapy, in 2 as second- line and in 1 as third-line after diagnosis of BM. Dose reduction was performed in 11 (61.1%) patients; major reasons were neutropenia and leukopenia. Grade III neutropenia and Grade II trombocytopenia rates were 33.3% and 16.7% respectively. Overall response rate (ORR; complete+partial response rate) was 33.4% (n=6) for the entire study population; triple negative patients achieved an 66.6% ORR while hormone receptor (HR) positive patients had 25% and HER2 positive patients 12.5%. Median progression-free survival was 5.6 months (2.4-8.8 months, 95%CI) and longer in patients with triple negative breast cancer (TNBC) (median 7.4 months, 95%CI, 2.4-12.3 months) than the patients with other subtypes (median 5 months for HER2 positive and 3.6 months for HR positive patients). Median PFS of the patients with TNBC who received this regimen as first-line was 9.2 months (5.2-13.2 months, 95%CI). Cisplatin plus Gemcitabine may be a treatment option for patients with BM from breast cancer. Longer PFS and higher response rates are results that support the usage of this regimen especially for the triple negative subtype. However, further prospective and randomized trials are clearly required to provide more exact information.


Role of cyclic ADP-ribose in ATP-activated potassium currents in alveolar macrophages.
There is growing evidence that extracellular ATP causes a dramatic change in the membrane conductance of a variety of inflammatory cells. In the present study, using the nystatin perforated patch recording configuration, we found that ATP (0.3-30 microM) induced a transient outward current in a concentration-dependent manner and that the reversal potential of the ATP-induced outward current was close to the K+ equilibrium potential, indicating that the membrane behaves like a K+ electrode in the presence of ATP. The first application of ATP to alveolar macrophages perfused with Ca2+-free external solution could induce the outward current, but the response to ATP was diminished with successive applications. Intracellular perfusion with a Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid, also diminished the response. When cyclic ADP-ribose (cADPR) was applied to the macrophage cytoplasm, a transient outward current was elicited. Thereafter, the successive outward current was inhibited, suggesting the involvement of cADPR in the response. Intracellular perfusion with inositol 1,4, 5-trisphosphate also induced a transient outward current, but the successive current was not inhibited. The ATP-induced outward current was abolished when 8-amino-cADPR (as a blocker of cADPR, 10(-6)-10(-5) M) was introduced into the cytoplasm. Homogenates of alveolar macrophages showed both ADP-ribosyl cyclase and cADPR hydrolase activities, and CD38 (ADP-ribosyl cyclase/cADPR hydrolase) expression was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analyses. These results indicate that ATP activates K+ currents by releasing Ca2+ from cADPR-sensitive internal Ca2+ stores.


Purification and characterization of leucocidin from Pseudomonas aeruginosa.
Leucocidin from Pseudomonas aeruginosa strain 158 was released from bacteria by autolysis and purified 19-fold by ammonium sulphate precipitation (20% saturation) and combined 'tandem' gel filtration on Sephadex G-100 superfine and Bio Gel P-100. The product gave a single band (mol. wt. 27000) after poly-acrylamide gel electrophoresis with sodium dodecyl sulphate (SDS). However, it was separated into two active peaks (pI 5-0 and 5-2) by isoelectric focusing, and into five bands by disc electrophoresis without SDS. All bands contained leucocidic activity of about the same specific activity and retained their homogeneity. The purified toxin was thermolabile and was inactivated by pronase, but not by several other proteases. The ultraviolet light absorbancy was typical of proteins. Antibodies directed against leucocidin were detected by passive haemagglutination and by toxin-neutralization. These antibodies inhibited the cytotoxic action of leucocidin bound to granulocytes. The toxin damaged all tested leucocytes (granulocytes of various animal species and lymphocytes of humans) and a number of tissue cultures, but was ineffective against erythrocytes, thrombocytes and isolated granules from polymorphonuclear leucocytes. The intravenous lethal dose for mice was about 1 mug.


Orientation dependent wavefront correction system under grazing incidence.
Making use of the stretching effect of grazing incident laser beam, a novel method of wavefront correction was promoted. Without adding any extra beam expanding components, aberrations of wavefront could achieve satisfying correction by two grazing reflections along orthogonal directions on the deformable mirrors. The stretching effect expanded the beam size along grazing direction and the orientation dependent varying aberrations were well compensated as more actuators took effect in the correction process. Analysis showed that the fitting coefficient of all the first 30 order Zernike polynomials could be controlled within 5% by this method.


Homocysteine as a risk factor for development of microalbuminuria in type 2 diabetes.
Kidney function is critical in homocysteine clearance, and plasma homocysteine level is frequently increased in patients with renal failure. On the other hand, recent studies in animals have shown that hyperhomocysteinemia induces renal injury. In this study, we determined whether hyperhomocysteinemia can be a risk factor for the development of microalbuminuria in patients with type 2 diabetes. A nested case-control study. Of 887 patients with type 2 diabetes who did not have microalbuminuria at baseline, 76 developed microalbuminuria during follow-up (mean, 36.0 +/- 11.7 months; range, 18 to 76 months). The control group consisted of 152 age- and sex-matched subjects who did not develop microalbuminuria. Baseline plasma homocysteine concentrations were measured in stored samples. Baseline plasma homocysteine concentrations and mean HbA1C levels during follow-up were significantly higher in patients who developed microalbuminuria than in those who remained normoalbuminuric. Multivariate logistic regression analysis showed that baseline plasma homocysteine level and mean HbA1C were independent predictors of microalbuminuria in type 2 diabetes. Hyperhomocysteinemia was associated with increased risk of microalbuminuria in patients with type 2 diabetes supporting the concept that hyperhomocysteinemia has an etiologic role in the pathogenesis of diabetic nephropathy.


[Inflammatory Bowel Disease and Pregnancy].
The incidence of chronic inflammatory bowel disease is highest in the childbearing age. The diagnosis itself, but also the various treatment options available, often lead to uncertainties in affected women with regard to fertility, pregnancy and breastfeeding. Not only by providing affected women with good information, but also by planning and accompanying the pregnancy, optimal conditions for a complication-free pregnancy can be achieved.


Ecdysteroid glycosides: identification, chromatographic properties, and biological significance.
Ecdysteroid glycosides are found in both animals and plants. The chromatographic behavior of these molecules is characteristic, as they appear much more polar than their corresponding free aglycones when analyzed by normal-phase high-performance liquid chromatography (HPLC), whereas the presence of glycosidic moieties has a very limited (if any) impact on polarity when using reversed-phase HPLC. Biological activity is greatly reduced because the presence of this bulky substituent probably impairs the interaction with ecdysteroid receptor(s). 2-Deoxy-20-hydroxyecdysone 22-O-beta-D-glucopyranoside, which has been isolated from the dried aerial parts of Silene nutans (Caryophyllaceae), is used as a model compound to describe the rationale of ecdysteroid glycoside purification and identification.


Evolutionary implications of non-neutral mitochondrial genetic variation.
Sequence variation in mitochondrial DNA (mtDNA) was traditionally considered to be selectively neutral. However, an accumulating body of evidence indicates that this assumption is invalid. Furthermore, recent advances indicate that mtDNA polymorphism can be maintained within populations via selection on the joint mitochondrial-nuclear genotype. Here, we review the latest findings that show mitochondrial and cytoplasmic genetic variation for life-history traits and fitness. We highlight the key importance of the mitochondrial-nuclear interaction as a unit of selection and discuss the consequences of mitochondrially encoded fitness effects on several key evolutionary processes. Our goal is to draw attention to the profound, yet neglected, influence of the mitochondrial genome on the fields of ecology and evolution.


Parachordoma of soft tissues of the arm: a very rare tumour.
Parachordoma is an infrequent neoplasm that bears some histologic resemblance to chordoma. It affects both sexes, occurs typically during the fourth decade of life, and tends to present as a slow-growing painless mass at the level of the soft tissues of the extremities. Diagnosis should be based on immunohistochemical and cytogenetic studies, as the findings of imaging techniques are often unspecific. Although it is considered a benign lesion, its behavior tends to be locally aggressive, with reports of a recurrence rate of up to 20% and of several cases of metastasis. Fewer than 60 cases have been published in the English-speaking literature. In this paper we present the case of a 32-year-old male with a two-year history of parachordoma in the right wrist.


Identifying hosts of families of viruses: a machine learning approach.
Identifying emerging viral pathogens and characterizing their transmission is essential to developing effective public health measures in response to an epidemic. Phylogenetics, though currently the most popular tool used to characterize the likely host of a virus, can be ambiguous when studying species very distant to known species and when there is very little reliable sequence information available in the early stages of the outbreak of disease. Motivated by an existing framework for representing biological sequence information, we learn sparse, tree-structured models, built from decision rules based on subsequences, to predict viral hosts from protein sequence data using popular discriminative machine learning tools. Furthermore, the predictive motifs robustly selected by the learning algorithm are found to show strong host-specificity and occur in highly conserved regions of the viral proteome.


Neurocognitive reward processes measured via event-related potentials are associated with binge-eating disorder diagnosis and ecologically-assessed behavior.
Altered reward processing has been implicated in the onset and maintenance of binge-eating disorder (BED). However, it is unclear which precise neurocognitive reward processes may contribute to BED. In the present study, 40 individuals with BED and 40 age-, sex-, and BMI-matched controls completed a reward (incentive delay) task while their neural activity was recorded using electroencephalography (EEG). Individuals with BED also completed a 10-day ecological momentary assessment (EMA) protocol assessing binge-eating behavior in the natural environment. Event-related potential (ERP) analysis of the EEG indicated that individuals with BED had stronger anticipatory (CNV) and outcome-related (RewP) neural reward activity to food and monetary rewards, compared to controls. However, within the BED group, greater frequency of binge eating during the EMA protocol was associated with stronger anticipatory (CNV) but weaker outcome-related (RewP) neural reward activity. These associations within the BED group were unique to food, and not monetary, rewards. Although preliminary, these results suggest that both anticipatory ("wanting") and outcome ("liking") reward processes may be generally amplified in BED. However, they also suggest that among individuals with BED, disorder severity may be associated with increased anticipatory reward processes ("wanting"), but relatively decreased reward-outcome processing ("liking"), of food rewards specifically.


Occasional seizures, epilepsy, and inborn errors of metabolism.
Seizures are a common paediatric problem, with inborn errors of metabolism being a rare underlying aetiology. The clinical presentation of inborn errors of metabolism is often associated with other neurological symptoms, such as hypotonia, movement disorders, and cognitive disturbances. However, the occurrence of epilepsy associated with inborn errors of metabolism represents a major challenge that needs to be identified quickly; for some cases, specific treatments are available, metabolic decompensation might be avoided, and accurate counselling can be given about recurrence risk. Some clinical presentations are more likely than others to point to an inborn error of metabolism as the cause of seizures. Knowledge of important findings at examination, and appropriate biochemical investigation of children with seizures of uncertain cause, can aid the diagnosis of an inborn error of metabolism and ascertain whether or not the seizures are amenable to specific metabolic treatment.


Lung Cancer Mimicking Aspergilloma: A Case Report.
An aspergilloma is a conglomeration of Aspergillus hyphae, fibrin, mucus, and cellular debris, typically found within a pulmonary cavity or ectatic bronchus. Computerized tomography (CT) scans often depict a cavity containing a solid mass and a notable crescent sign. Though these signs are indicative of aspergilloma, the European Respiratory Society emphasizes the need for a more detailed diagnostic criteria. A patient with a history of hemoptysis was initially diagnosed with an aspergilloma based on CT chest findings, showing a cavitary lesion in the left upper lobe with an intracavitary lobular opacity. Post resection, histological examination contradicted the initial diagnosis, revealing lung cancer instead. This case underscores the importance of tissue diagnosis from the outset or employing a multifaceted diagnostic criteria encompassing radiological findings, serology and microbiology tests. In the absence of an initial tissue diagnosis, rigorous follow-up, including early interval scanning, is crucial.


[Role of spiral computed tomography in the assessment of the bone and soft tissue structures of the spine in the postoperative period of degenerative diseases and traumas].
The spiral computed tomography (SCT) was used in examinations of 59 patients with symptoms of neurological disorders at the postoperative period after discectomy, and 82 casualties and 24 patients with degenerative-dystrophic lesions of the spine after correcting-stabilizing operations with plasty of the vertebra with autobone, biositall-XK. An examination of this category of patients and casualties in the nearest and remote terms after operation improves the potentials of SCT-diagnostics of recurrent hernias, epidural fibrosis, spondylites, central and lateral stenoses and allows control of osteoreparation and remodelling of the spine. The improved pathogenetical treatment in these cases shortens the period of disability and does not result in persistent invalidism of the patients.


[Rapamycin and CCI-779].
Rapamycin (sirolimus) is a macrolide, related to cyclosporine with immunosuppressive properties and antiproliferative activity in various human tumor cells lines and tumor xenograft models. The cytosolic kinase mTOR which controls the initiation of the translation of messenger RNA is the main known target of rapamycin. During clinical studies, rapamycin given by oral route as immunosuppressant did not show dose-limited toxicity and only asymptomatic thrombopenia and hyperlipemia were observed. In murine models, best antitumoral activity was observed using parental routes. CCI-779, an analog formulated for intravenous use has antitumor activity without significant immunosuppressive property in mice and is currently in phase I trials in man.


The learning curve for transradial percutaneous coronary intervention among operators in the United States: a study from the National Cardiovascular Data Registry.
Adoption of transradial percutaneous coronary intervention (TRI) in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator TRI volume and procedural metrics and outcomes. We used CathPCI Registry data from July 2009 to December 2012 to identify new radial operators, defined by an exclusively femoral percutaneous coronary intervention approach for 6 months after their first percutaneous coronary intervention in the database and ≥15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed by using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54 561 TRI procedures performed at 704 sites, 942 operators performed 1 to 10 procedures, 942 operators performed 11 to 50 procedures, 375 operators performed 51 to 100 procedures, and 148 operators performed 101 to 200 procedures. As radial caseload increased, more TRIs were performed in women, in patients presenting with ST-segment elevation myocardial infarction, and for emergency indications. Decreased fluoroscopy time and contrast use were nonlinearly associated with greater operator TRI experience, with faster reductions observed for newer (<30-50 cases) compared with more experienced (>30-50 cases) operators. Procedure success was high, whereas mortality, bleeding, and vascular complications remained low across TRI volumes. As operator TRI volume increases, higher-risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30 to 50 cases.


A positively temperature-responsive, substrate-selective Ag nanoreactor.
An original Ag nanoreactor capable of positively temperature-responsive and substrate-selective catalysis was prepared in this study. This nanoreactor was made of Ag nanoparticles encapsulated in a 4-nitrophenol (NP)-imprinted polymer matrix that exhibited a temperature-sensitive interpolymer interaction between poly(acrylamide) (PAAm) and (2-acrylamide-2-methylpropanesulfonic acid) (PAMPS). At relatively low temperatures (such as 20 degrees C), this nanoreactor did not demonstrate significant NP-selective catalysis due to the interpolymer complexation between PAAm and PAMPS, which caused shrinking in the imprinted networks. Conversely, at relatively high temperatures (such as 40 degrees C), this nanoreactor provided significant NP-selective catalysis resulting from the dissociation of the interpolymer complexes between PAAm and PAMPS. Unlike traditional Ag nanoreactors, which lack positively temperature-responsive catalysis or substrate-selective ability, this unique nanoreactor employed both the imprinting of the substrate molecule (i.e., NP) and a temperature-sensitive PAAm/PAMPS network, thereby making positively temperature-responsive, substrate-selective catalysis feasible.


Regulation of conductive Cl- transport in human fibroblasts.
Under normal growth conditions, approximately 20% of the efflux of Cl- from human fibroblasts occurs via an electrically conductive pathway or Cl- channel. This basal Cl- conductance is insensitive to the Cl- -anion exchange inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and to the Cl- -cation cotransport inhibitor bumetanide. Exposure of the cells to dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP) for 15 min increases the electrically conductive component of Cl- efflux by approximately 20%. Unlike the basal Cl- conductance, the cAMP-activated channel is DIDS sensitive, indicating that cAMP activates a different Cl- pathway from the one responsible for the basal Cl- conductance. Elevation of intracellular Ca2+ by addition of the ionophore A23187 also stimulates Cl- efflux via a DIDS inhibitable, electrically conductive Cl- pathway. That the cAMP- and Ca2+-stimulated pathways are different is suggested by the observation that simultaneous exposure of cells to optimal levels of dibutyryl cAMP and A23187 results in an increased Cl- efflux equal to the sum of the two factors acting independently. Prostaglandin E1, a known activator of adenylate cyclase, also elevates the levels of intracellular free Ca2+ in these cells and concomitantly activates both the cAMP- and the Ca2+-stimulated Cl- channels. Although regulated, Cl- channels are known to function in the modulation of nerve and muscle excitability, their role in fibroblast function is not clear.


Distribution of phosphorylated TrkB receptor in the mouse hippocampal formation depends on sex and estrous cycle stage.
Tropomyosin-related kinase B receptor (TrkB) is a neurotrophin receptor important for the synaptic plasticity underlying hippocampal-dependent learning and memory. Because this receptor is widely expressed in hippocampal neurons, the precise location of TrkB activation is likely important for its specific actions. The goal of this study was to identify the precise sites of TrkB activation in the mouse hippocampal formation and to determine any changes in the distribution of activated TrkB under conditions of enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal excitability. Using electron microscopy, we localized TrkB phosphorylated at tyrosine 816 (pTrkB) in the hippocampal formation of male and female mice under conditions of naturally low circulating estradiol and naturally high circulating estradiol, when BDNF expression, TrkB signaling, and synaptic plasticity are enhanced. To compare relative amounts of pTrkB in each group, we counted profiles containing pTrkB-immunoreactivity (pTrkB-ir) in all hippocampal subregions. pTrkB-ir was in axons, axon terminals, dendrites, and dendritic spines of neurons in the hippocampal formation, but the majority of pTrkB-ir localized to presynaptic profiles. pTrkB-ir also was abundant in glial profiles, which were further identified as microglia using immunofluorescence and confocal microscopy. Axonal and glial pTrkB-ir and pTrkB-ir in the CA1 stratum radiatum were more abundant in high-estradiol states (proestrus females) than low-estradiol states (estrus and diestrus females and males). These findings suggest that presynaptic TrkB is positioned to modulate estradiol-mediated and BDNF-dependent synaptic plasticity. Furthermore, they suggest a novel role for TrkB in microglial function in the neuroimmune system.


Analysis of volatile oil composition of Citrus aurantium L. by microwave-assisted extraction coupled to headspace solid-phase microextraction with nanoporous based fibers.
Nanoporous silica was prepared and functionalized with amino propyl-triethoxysilane to be used as a highly porous fiber-coating material for solid-phase microextraction (SPME). The prepared nanomaterials were immobilized onto a stainless steel wire for fabrication of the SPME fiber. The proposed fiber was evaluated for the extraction of volatile component of Citrus aurantium L. leaves. A homemade microwave-assisted extraction followed by headspace (HS) solid-phase apparatus was used for the extraction of volatile components. For optimization of factors affecting the extraction efficiency of the volatile compounds, a simplex optimization method was used. The repeatability for one fiber (n = 4), expressed as RSD, was between 3.1 and 8.6% and the reproducibility for five prepared fibers was between 10.1 and 14.9% for the test compounds. Using microwave-assisted distillation HS-SPME followed by GC-MS, 53 compounds were separated and identified in C. aurantium L., which mainly included limonene (62.0%), linalool (7.47%), trans-β-Ocimene (3.47%), and caryophyllene (2.05%). In comparison to a hydrodistillation method, the proposed technique could equally monitor almost all the components of the sample, in an easier way, which was rapid and required a much lower amount of sample.


Deep insights into the network of acetate metabolism in anaerobic digestion: focusing on syntrophic acetate oxidation and homoacetogenesis.
Acetate is a pivotal intermediate product during anaerobic decomposition of organic matter. Its generation and consumption network is quite complex, which almost covers the most steps in anaerobic digestion (AD) process. Besides acidogenesis, acetogenesis and methanogenesis, syntrophic acetate oxidation (SAO) replaced acetoclastic methanogenesis to release the inhibition of AD at some special conditions, and the importance of considering homoacetogenesis had also been proved when analysing anaerobic fermentations. Syntrophic acetate-oxidizing bacteria (SAOB), with function of SAO, can survive under high temperature and ammonia/ volatile fatty acids (VFAs) concentrations, while, homoacetogens, performed homoacetogenesis, are more active under acidic, alkaline and low temperature (10°C-20°C) conditions, This review summarized the roles of SAO and homoacetogenesis in AD process, which contains the biochemical reactions, metabolism pathways, physiological characteristics and energy conservation of functional bacteria. The specific roles of these two processes in the subprocess of AD (i.e., acidogenesis, acetogenesis and methanogenesis) were also analyzed in detail. A two phases anaerobic digester is proposed for protein-rich waste(water) treatment by enhancing the functions of homoacetogens and SAOB compared to the traditional two-phases anaerobic digesters, in which the first phase is fermentation phase including acidogens and homoacetogens for acetate production, and second phase is a mixed culture coupling syntrophic fatty acids bacteria, SAOB and hydrogenotrophic methanogens for methane production. This review provides a new insight into the network on production and consumption of acetate in AD process.


Hierarchical Mechanisms of Lateral Interactions in High-Performance Fibers.
The processing conditions used in the production of advanced polymer fibers facilitate the formation of an oriented fibrillar network that consists of structures spanning multiple length scales. The irregular nature of fiber tensile fracture surfaces suggests that their structural integrity is defined by the degree of lateral (interfacial) interactions that exist within the fiber microstructure. To date, experimental studies have quantified interfacial adhesion between nanoscale fibrils measuring 10-50 nm in width, and the global fracture energy through applying peel loads to fiber halves. However, a more in-depth evaluation of tensile fracture indicates that fiber failure typically occurs at an intermediate length scale, involving fibrillation along interfaces between fibril bundles of a few 100s of nanometers in width. Interaction mechanisms at this length scale have not yet been studied, due in part to a lack of established experimental techniques. Here, a new focused ion beam-based sample preparation protocol is combined with nanoindentation to probe interfaces at the intermediate length scale in two high-performance fibers, a rigid-rod poly(p-phenylene terephthalamide) and a flexible chain ultrahigh molecular weight polyethylene fiber. Higher interfacial separation energy recorded in the rigid-rod fiber correlated with less intensive fibrillation during failure and is discussed in the context of fiber chemistry and processing. Power law scaling of the total absorbed interfacial separation energy at three different scales in the polyethylene fiber is observed and analyzed, and distinct energy absorption mechanisms, featuring a degree of self-similarity, are identified. The contribution of these mechanisms to the overall integrity of the fiber is discussed, and the importance of the intermediate scale is elucidated. Results from this study provide new insights into the mechanical implications of hierarchical lateral interactions and will aid in the development of novel fibers with further improved mechanical performance.


Periosteal BMP2 activity drives bone graft healing.
Bone graft incorporation depends on the orchestrated activation of numerous growth factors and cytokines in both the host and the graft. Prominent in this signaling cascade is BMP2. Although BMP2 is dispensable for bone formation, it is required for the initiation of bone repair; thus understanding the cellular mechanisms underlying bone regeneration driven by BMP2 is essential for improving bone graft therapies. In the present study, we assessed the role of Bmp2 in bone graft incorporation using mice in which Bmp2 has been removed from the limb prior to skeletal formation (Bmp2(cKO)). When autograft transplantations were performed in Bmp2cKO mice, callus formation and bone healing were absent. Transplantation of either a vital wild type (WT) bone graft into a Bmp2(cKO) host or a vital Bmp2(cKO) graft into a WT host also resulted in the inhibition of bone graft incorporation. Histological analyses of these transplants show that in the absence of BMP2, periosteal progenitors remain quiescent and healing is not initiated. When we analyzed the expression of Sox9, a marker of chondrogenesis, on the graft surface, we found it significantly reduced when BMP2 was absent in either the graft itself or the host, suggesting that local BMP2 levels drive periosteal cell condensation and subsequent callus cell differentiation. The lack of integrated healing in the absence of BMP2 was not due to the inability of periosteal cells to respond to BMP2. Healing was achieved when grafts were pre-soaked in rhBMP2 protein, indicating that periosteal progenitors remain responsive in the absence of BMP2. In contrast to the requirement for BMP2 in periosteal progenitor activation in vital bone grafts, we found that bone matrix-derived BMP2 does not significantly enhance bone graft incorporation. Taken together, our data show that BMP2 signaling is not essential for the maintenance of periosteal progenitors, but is required for the activation of these progenitors and their subsequent differentiation along the osteo-chondrogenic pathway. These results indicate that BMP2 will be among the signaling molecules whose presence will determine success or failure of new bone graft strategies.


Interaction between the protective effects of cannabidiol and palmitoylethanolamide in experimental model of multiple sclerosis in C57BL/6 mice.
Cannabinoids (CBs) have recently been approved to exert broad anti-inflammatory activities in experimental models of multiple sclerosis (MS). It has been demonstrated that these compounds could also have effects on neurodegeneration, demyelination, and autoimmune processes occurring in the pathology of MS. However, the clinical use of CBs is limited by their psychoactive effects. Among cannabinoid compounds, cannabidiol (CBD) and palmitoylethanolamide (PEA) have no psychotropic activities. We induced experimental autoimmune encephalomyelitis (EAE), a model of MS, by injecting myelin oligodendrocyte glycoprotein (MOG) to C57BL/6 mice. We assessed the effects of CBD, PEA, and co-administration of CBD and PEA on neurobehavioral scores, immune cell infiltration, demyelination, axonal injury, and the expression of inflammatory cytokines by using histochemistry methods and real-time RT-PCR. Treatment with either CBD (5mg/kg) or PEA (5mg/kg) during disease onset reduced the severity of the neurobehavioral scores of EAE. This effect of CBD and PEA was accompanied by diminished inflammation, demyelination, axonal damage and inflammatory cytokine expression while concurrent administration of CBD (5mg/kg) and PEA (5mg/kg) was not as effective as treatment with either drug per se. These results suggest that, CBD and PEA, non-psychoactive CBs, attenuate neurobehavioral deficits, histological damage, and inflammatory cytokine expression in MOG-immunized animals. However, there is an antagonistic interaction between CBD and PEA in protection against MOG-induced disease.


The Role of FoxC2 Transcription Factor in Tumor Angiogenesis.
Much has been learned about the mechanisms underlying tumor angiogenesis, and therapies that target vascular endothelial growth factor (VEGF) to limit tumor angiogenesis and subsequent disease progression have recently been approved. However, the transcriptional mechanisms that regulate pathological angiogenesis remain largely unknown. FoxC2, a member of the Forkhead box (Fox) transcription factor family, is critical for vascular formation during development, and recent studies have shown that FoxC2 is expressed in the endothelium of tumors in both humans and mice. In a B16 mouse melanoma model, Foxc2 deficiency reduced tumor growth and neovascularization and was associated with impairments in mural-cell coverage and increases in endothelial-cell apoptosis in tumor blood vessels. FoxC2 is also expressed by tumor cells in human breast, colonic, and esophageal cancer and participates in the epithelial-mesenchymal transition (EMT), a key process that leads to the invasion and metastasis of aggressive tumors. Collectively, these observations suggest that FoxC2 is essential for tumor angiogenesis and disease progression and that FoxC2 may be a viable target for cancer therapy.


C-Reactive Protein (CRP) is a Promising Diagnostic Immunohistochemical Marker for Intrahepatic Cholangiocarcinoma and is Associated With Better Prognosis.
Differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) from its histologic mimickers, especially metastatic adenocarcinomas of gastric and pancreatic origin, is a great challenge for pathologists. In this study, through bioinformatics analysis of data from The Cancer Genome Atlas and Gene Expression Omnibus, we identified C-reactive protein (CRP) as a candidate marker to differentiate iCCA from other adenocarcinomas and validated its diagnostic performance by immunohistochemistry in a large cohort of clinical samples including 103 iCCAs, 384 other adenocarcinomas, and 34 liver metastases of various origins. The sensitivity and specificity of CRP expression in the diagnosis of iCCA were 75.7% and 91.1% when using tissue microarrays and 93.3% and 88.2% when using whole tissue sections, respectively. We also compared the diagnostic performance of CRP with N-cadherin, a previously reported marker for iCCA. The sensitivity and specificity of N-cadherin were 54.4% and 92.2% when using tissue microarrays and 80.0% and 88.2% when using whole tissue sections, respectively. The sensitivity of CRP was higher than that of N-cadherin, whereas their specificity was similar. CRP expression was associated with mass-forming gross type (P<0.001), absence of perineural invasion (P=0.002), and N-cadherin expression (P<0.001). CRP expression was also associated with better overall survival (P=0.002) and longer recurrence-free time (P=0.032) after surgery. Our study suggests that CRP is a promising immunohistochemical marker to differentiate iCCA from other adenocarcinomas. Compared with N-cadherin, CRP showed higher sensitivity and similar specificity. CRP expression was associated with better prognosis in iCCA.


Differential diagnosis and treatment strategies for biologic complications and failing oral implants: a review of the literature.
The aim of this article was to review the literature on differential diagnosis and treatment of biologic complications and failing implants. All types of publications, with the exception of abstracts, published in English up to December 1998, were included. A multi-layered search strategy was used. Controlled clinical trials (CCTs) were searched in the Cochrane Oral Health Group's Specialized Register of Trials. This database contains all CCTs identified in MEDLINE and EMBASE. PubMed was searched using various key words and the "related articles" feature. All identified publications were obtained and none were excluded. Infection, impaired healing, and overload are considered the major etiologic factors for the loss of oral implants. Only a few clinical and animal investigations were found that tested the validity of the proposed therapeutic approaches. The treatment of failing implants is still based mainly on empirical considerations, often derived from periodontal research, from data extrapolated from in vitro findings, or from anecdotal case reports performed on a trial-and-error basis.


Cognitive restructuring of gambling-related thoughts: A systematic review.
Gamblers' thoughts have a fundamental influence on their gambling problem. Cognitive restructuring is the intervention of choice to correct those thoughts. However, certain difficulties are noted in the application of cognitive restructuring techniques and the comprehension of their guidelines. Furthermore, the increase of skill game players (e.g. poker) entering treatment creates a challenge for therapists, as these gamblers present with different thoughts than those of the gamblers usually encountered in treatment (e.g. chance-only games like electronic gambling machines). This systematic review aims to describe how cognitive restructuring is carried out with gamblers based on the evidence available in empirical studies that include cognitive interventions for gambling. Of the 2607 studies collected, 39 were retained. The results highlight exposure as the most frequently used technique to facilitate identification of gambling-related thoughts (imaginal=28.2%; in vivo=10.3%). More than half of the studies (69.2%) clearly reported therapeutic techniques aimed to correct gamblers' thoughts, of which 37% involved visual support to challenge those thoughts (e.g. ABC log). Of the 39 studies retained, 48.7% included skill game players (i.e., poker, blackjack, sports betting) in their sample. However, none of these studies mentioned whether cognitive restructuring had been adapted for these gamblers. Several terms referring to gamblers' thoughts were used interchangeably (e.g. erroneous, dysfunctional or inadequate thoughts), although each of these terms could refer to specific content. Clinical implications of the results are discussed with regard to the needs of therapists. This review also suggests recommendations for future research.


Multivalent agents containing 1-substituted 2,3,4-trihydroxyphenyl moieties as novel synthetic polyphenols directed against HIV-1.
The synthesis and the assessment of the anti-HIV activity of a set of molecules inspired by the multivalent structures of some naturally-occurring polyphenols (tannins) are reported. Different multibranched scaffolds have been derived from pentaerythritol as the central core which distribute spatially synthetic polyphenolic subunits based on 1-substituted 2,3,4-trihydroxyphenyl moieties. A tetrapodal compound () bearing four N-(2,3,4-trihydroxyphenyl)amide groups, exhibits remarkable selective activity against HIV-1 with EC50 values in the micromolar scale, in the same range as those reported for the most representative anti-HIV tannins. Preliminary SAR studies emphasize the importance of the 1-substituted 2,3,4-trihydroxyphenyl moiety, the presence of an amide as the linker and the multivalent architecture of these molecules, since the anti-HIV activity increases with the number of polyphenolic moieties. The data support the interest in synthetic polyphenols and represent a promising starting point for further design and development of selective HIV-1 inhibitors.


Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin.
To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 μg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.


Gastrointestinal sarcomas. Analysis of prognostic factors.
Clinical and pathologic data from 51 patients with primary sarcomas of the gastrointestinal tract treated from 1951 through 1984 were reviewed to determine clinical presentation, histologic features, treatment, and prognostic factors. The most common signs and symptoms were abdominal pain (62%), gastrointestinal bleeding (40%), and/or abdominal mass (38%). The primary site was stomach in 50%, small bowel in 30%, colorectum in 15%, and esophagus in 5%. Virtually all the sarcomas were leiomyosarcomas. Distribution was uniform among the three histologic grades; although 88% of Grade 1 tumors could be completely excised, only 35% of Grade 3 tumors could be completely resected. The 5-year survival rate was 75% for Grade 1 tumors, 16% for Grade 2 tumors, and 28% for Grade 3 tumors (p = 0.0013, Grade 1 vs. 2 and 3). Thirty of the 51 patients (59%) had curative resection with an operative morbidity rate of 24% and an operative mortality rate of 12%; at 5 years the disease-free survival rate was 58% and the overall survival rate was 63% (48% at 10 years). Eleven patients (42%) had recurrent disease develop at a median interval of 2 years after complete tumor excision. Twenty-one patients (41%) had partial excision or biopsy only of their tumors with an operative morbidity rate of 28%, operative mortality rate of 8%, and median survival of only 9 months. Overall, patients whose tumors were confined to the site of origin had a 58% 5-year survival rate compared with 20% for those whose tumors had invaded adjacent organs (p less than 0.05). If the tumor was less than 10 cm in size, the 5-year survival rate was 78%, significantly better than the 38% for tumors greater than 10 cm (p = 0.03). These data suggest that histologic grade, local invasiveness, size, and extent of resection are the most important prognostic factors for patients with primary gastrointestinal sarcomas. Patients who have resection of all gross tumor, especially if it is well differentiated and localized, have a good prognosis.


Agrin isoforms with distinct amino termini: differential expression, localization, and function.
The proteoglycan agrin is required for postsynaptic differentiation at the skeletal neuromuscular junction, but is also associated with basal laminae in numerous other tissues, and with the surfaces of some neurons. Little is known about its roles at sites other than the neuromuscular junction, or about how its expression and subcellular localization are regulated in any tissue. Here we demonstrate that the murine agrin gene generates two proteins with different NH(2) termini, and present evidence that these isoforms differ in subcellular localization, tissue distribution, and function. The two isoforms share approximately 1,900 amino acids (aa) of common sequence following unique NH(2) termini of 49 or 150 aa; we therefore call them short NH(2)-terminal (SN) and long NH(2)-terminal (LN) isoforms. In the mouse genome, LN-specific exons are upstream of an SN-specific exon, which is in turn upstream of common exons. LN-agrin is expressed in both neural and nonneural tissues. In spinal cord it is expressed in discrete subsets of cells, including motoneurons. In contrast, SN-agrin is selectively expressed in the nervous system but is widely distributed in many neuronal cell types. Both isoforms are externalized from cells but LN-agrin assembles into basal laminae whereas SN-agrin remains cell associated. Differential expression of the two isoforms appears to be transcriptionally regulated, whereas the unique SN and LN sequences direct their distinct subcellular localizations. Insertion of a "gene trap" construct into the mouse genome between the LN and SN exons abolished expression of LN-agrin with no detectable effect on expression levels of SN-agrin or on SN-agrin bioactivity in vitro. Agrin protein was absent from all basal laminae in mice lacking LN-agrin transcripts. The formation of the neuromuscular junctions was as drastically impaired in these mutants as in mice lacking all forms of agrin. Thus, basal lamina-associated LN-agrin is required for neuromuscular synaptogenesis, whereas cell-associated SN-agrin may play distinct roles in the central nervous system.


Menin associates with FANCD2, a protein involved in repair of DNA damage.
Multiple endocrine neoplasia type I (MEN1) is an inherited tumor syndrome characterized by tumors in multiple endocrine organs including the parathyroids, pancreatic islets, and the pituitary. The gene mutated in MEN1 patients, Men1, encodes a protein of 610 amino acid residues, menin, and mutations in the Men1 gene lead to the MEN1 syndrome. Although the chromosomal instability in the peripheral lymphocytes from the MEN1 patients has been reported previously, it is not clear whether menin is involved in repair of DNA damage. Here we show that menin specifically interacts with FANCD2, a protein encoded by a gene involved in DNA repair and mutated in patients with an inherited cancer-prone syndrome, Fanconi anemia. The interaction between menin and FANCD2 is enhanced by gamma-irradiation. Moreover, loss of menin expression in mouse embryonic fibroblasts leads to increased sensitivity to DNA damage. Furthermore, menin is localized to chromatin and nuclear matrix, and the association with nuclear matrix is enhanced by gamma-irradiation. Together, these results suggest that menin plays a critical role in repair of DNA damage in concert with FANCD2.


Adrenomedullin relaxes rat uterine artery: mechanisms and influence of pregnancy and estradiol.
Uterine arteries play a major role in regulating uteroplacental blood flow. Failure to maintain blood flow to the uteroplacental compartment during pregnancy often results in intrauterine growth retardation. Immunohistochemical staining of adrenomedullin (AM), an endogenous vasoactive peptide, in uterine artery was intense in pregnant compared to nonpregnant rats, but it is not known whether AM directly relaxes uterine artery or not. In this study, we elucidated the mechanisms of uterine artery relaxation by AM and its regulation by pregnancy and female sex steroids. AM was able to relax uterine artery, and this relaxation was influenced positively by pregnancy and estradiol as evidenced by the increased pD(2) and E(max) values of AM. Both pregnancy and estradiol treatment to ovariectomized rats amplified RAMP(3) expression in uterine arteries while progesterone had no effect. AM-induced uterine artery relaxation is predominantly endothelium-dependent. The AM receptor antagonist CGRP(8-37) is more potent than AM(22-52) in inhibiting the AM relaxation, indicating the involvement of AM(2) receptor subtype. Moreover, AM uses the classical nitric oxide-cyclic guanosine monophosphate pathway along with K(Ca) channels to mediate the vasodilatory effect in uterine artery. In conclusion, sensitivity of uterine artery to AM-induced relaxation is increased with pregnancy or estradiol treatment by increasing RAMP(3) expression, suggesting an important role for AM in regulating the uterine hemodynamics, probably maintaining uterine blood flow during pregnancy and in pre- and postmenopausal cardiovascular adaptation differences.


Genetic analysis of families of patients with Behçet's syndrome: data incompatible with autosomal recessive inheritance.
Data on families with Behçet's syndrome were analysed to test a hypothesis of autosomal recessive inheritance. Fifteen families from the UK and nine from Turkey were included. There were 27 individuals with Behçet's syndrome according to the Japanese criteria and 119 unaffected individuals. There were no affected parents in the families. The 'goodness of fit' test of Elandt-Johnson was applied to the distribution of affected individuals in these families, and the data were found to be incompatible with autosomal recessive inheritance. HLA associations were also examined in patients and relatives, and this led to re-examination of previously published data on HLA associations with Behçet's syndrome.


A polyclonal antibody to the prepore loop of transient receptor potential vanilloid type 1 blocks channel activation.
Transient receptor potential vanilloid type 1 (TRPV1) can be activated by multiple chemical and physical stimuli such as capsaicin, anandamide, protons, and heat. Capsaicin interacts with the binding pocket constituted by transmembrane regions 3 and 4, whereas protons act through residues in the prepore loop of TRPV1. Here, we report on characterization of polyclonal and monoclonal antibodies to the prepore loop of TRPV1. A rabbit anti-rat TRPV1 polyclonal antibody (Ab-156H) acted as a full antagonist of proton activation (IC(50) values for pH 5 and 5.5 were 364.68 +/- 29.78 and 28.31 +/- 6.30 nM, respectively) and as a partial antagonist of capsaicin, heat, and pH 6 potentiated chemical ligand (anandamide and capsaicin) activation (50-79% inhibition). Ab-156H antagonism of TRPV1 is not affected by the conformation of the capsaicin-binding pocket because it is equally potent at wild-type (capsaicin-sensitive) rat TRPV1 and its T550I mutant (capsaicin-insensitive). With the goal of generating monoclonal antagonist antibodies to the prepore region of human TRPV1, we used a recently developed rabbit immunization protocol. Although rabbit polyclonal antiserum blocked human TRPV1 activation, rabbit monoclonal antibodies (identified on the basis of selective binding to Chinese hamster ovary cells expressing human TRPV1) did not block activation by either capsaicin or protons. Thus, rabbit polyclonal antibodies against rat and human TRPV1 prepore region seem to partially lock or stabilize the channel in the closed state, whereas rabbit anti-human TRPV1 monoclonal antibodies bind to the prepore region but do not lock or stabilize the channel conformation.


Improving compliance with exercise in adolescents with insulin-dependent diabetes mellitus: results of a self-motivated home exercise program.
In this project we investigated the impact of a 12-week at-home aerobic fitness program on aerobic capacity and metabolic control of ten adolescents (four girls and six boys 12 to 14 years of age) with insulin-dependent diabetes mellitus. The adolescents had no prior experience with exercise training. The 45-minute program, designed by a physical therapist, consisted of a stretching, calisthenics, and "cool-down" routine set to popular music. It was taught to the youngsters in group sessions. Each adolescent was given audio- and videocassettes of the routine for home use that emphasized self-motivation in maintaining training. The youngsters were asked to exercise three times per week and were also taught how to adjust their insulin and diet for exercise. Aerobic fitness was determined by maximal oxygen uptake following a vigorous, continuous progressive cycling test; metabolic control was measured by glycosylated hemoglobin values. All of the adolescents reported greater than 85% completion of the program. The youngsters displayed a correspondingly significant increase in aerobic fitness as measured by maximal oxygen uptake: 40.39 +/- 8.87 v 44.86 +/- 12.89 mL/kg/min. Glycosylated hemoglobin levels (mean +/- SD) for the entire group were significantly reduced after the program (11.41 +/- 4.47% v 10.01 +/- 3.21%). Results of this study indicate that nonathletic adolescents with insulin-dependent diabetes mellitus can engage in self-motivated exercise training at home. If properly designed, such programs can improve aerobic fitness and may contribute to improvement in diabetes control.


In vitro and in vivo study on the effect of antifungal agents on hematopoietic cells in mice.
Liposomal amphotericin B, voriconazole, and caspofungin are currently used for systemic and severe fungal infections. Patients with malignant diseases are treated with granulocyte-colony stimulating factor (G-CSF) for the recovery of granulocytes after chemotherapy or hematopoietic cell (HC) transplantation. Since they have a high incidence of fungal infections, they inevitably receive antifungal drugs for treatment and prophylaxis. Despite their proven less toxicity for various cell types comparatively with amphotericin B and the decrease in the number of leukocytes that has been reported as a possible complication in clinical studies, the effect of liposomal amphotericin B, voriconazole, and caspofungin on HCs has not been clarified. The present study aimed to examine the in vitro and in vivo effect of these three modern antifungals on HCs. Colony-forming unit (CFU) assays of murine bone marrow cells were performed in methylcellulose medium with or without cytokines and in the presence or absence of various concentrations of liposomal amphotericin B, voriconazole, and caspofungin. In the in vivo experiments, the absolute number of granulocytes was determined during leukocyte recovery in sublethally irradiated mice receiving each antifungal agent separately, with or without G-CSF. In vitro, all three antifungal drugs were nontoxic and, interestingly, they significantly increased the number of CFU-granulocyte-macrophage colonies in the presence of cytokines, at all concentrations tested. This was contrary to the concentration-dependent toxicity and the significant decrease caused by conventional amphotericin B. In vivo, the number of granulocytes was significantly higher with caspofungin plus G-CSF treatment, higher and to a lesser extent higher, but not statistically significantly, with voriconazole plus G-CSF and liposomal amphotericin B plus G-CSF treatments, respectively, as compared with G-CSF alone. These data indicate a potential synergistic effect of these antifungals with the cytokines, in vitro and in vivo, with subsequent positive effect on hematopoiesis.


Nociceptin modulates renal sympathetic nerve activity through a central action in conscious rats.
Nociceptin, an endogenous agonist of the opioid receptor-like(1) receptor, is expressed in the hypothalamus, where it is implicated in autonomic nervous system control. However, the central actions of nociceptin on sympathetic nerve activity have not been studied. We investigated the effect of intracerebroventricularly administered nociceptin (2-10 nmol) on blood pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious rats and sinoaortic-denervated (SAD) rats. Intracerebroventricularly administered nociceptin resulted in a dose-dependent decrease in mean arterial pressure (MAP) and HR in intact rats. RSNA decreased 31.5 +/- 2.1 and 19.9 +/- 5.0% at a dose of 2 and 5 nmol, respectively. In SAD rats, MAP, HR, and RSNA decreased in a dose-dependent manner, and the maximum responses were larger than those in intact rats. The decrease in HR induced by nociceptin was blocked by propranolol but not by atropine, which indicates that nociceptin is acting by inhibiting cardiac sympathetic outflow. These nociceptin-induced depressor and bradycardic responses were not antagonized by pretreatment with naloxone and nocistatin. These findings suggest that central nociceptin may have a functional role in regulating cardiovascular and sympathetic nervous systems.


Efficacy and tolerability of tropisetron in primary fibromyalgia--a highly selective and competitive 5-HT3 receptor antagonist. German Fibromyalgia Study Group.
Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen.


PcsR2 Is a LuxR-Type Regulator That Is Upregulated on Wheat Roots and Is Unique to Pseudomonas chlororaphis.
LuxR solos are common in plant-associated bacteria and increasingly recognized for playing important roles in plant-microbe interkingdom signaling. Unlike the LuxR-type transcriptional regulators of prototype LuxR/LuxI quorum sensing systems, luxR solos do not have a LuxI-type autoinducer synthase gene associated with them. LuxR solos in plant-pathogenic bacteria are important for virulence and in plant endosymbionts contribute to symbiosis. In the present study, we characterized an atypical LuxR solo, PcsR2, in the biological control species Pseudomonas chlororaphis 30-84 that is highly conserved among sequenced P. chlororaphis strains. Unlike most LuxR solos in the plant-associated bacteria characterized to date, pcsR2 is not associated with a proline iminopeptidase gene and the protein has an atypical N-terminal binding domain. We created a pcsR2 deletion mutant and used quantitative RT-PCR to show that the expression of pcsR2 and genes in the operon immediately downstream was upregulated ∼10-fold when the wild type strain was grown on wheat roots compared to planktonic culture. PcsR2 was involved in upregulation. Using a GFP transcriptional reporter, we found that expression of pcsR2 responded specifically to root-derived substrates as compared to leaf-derived substrates but not to endogenous AHLs. Compared to the wild type, the mutant was impaired in the ability to utilize root carbon and nitrogen sources in wheat root macerate and to colonize wheat roots. Phenazine production and most biofilm traits previously shown to be correlated with phenazine production also were diminished in the mutant. Gene expression of several of the proteins in the phenazine regulatory network including PhzR, Pip (phenazine inducing protein) and RpeA/RpeB were reduced in the mutant, and overexpression of these genes in trans restored phenazine production in the mutant to wild-type levels, indicating PcsR2 affects the activity of the these regulatory genes upstream of RpeA/RpeB via an undetermined mechanism. Our results indicate PcsR2 upregulates the expression of the adjacent operon in response to unknown wheat root-derived signals and belongs to a novel subfamily of LuxR-type transcriptional regulators found in sequenced P. chlororaphis strains.


Evaluation of cold chain system in Chandigarh during PPI campaign 2001-2002.
To evaluate the maintenance of cold chain system (CCS) in intensified pulse polio immunization (IPPI) programme, during December 2001 and January 2002 in Union Territory (UT) Chandigarh. A Cross sectional time bound study was conducted in seven centres, where OPV vials were stored prior to IPPI and 20 IPPI Booths in UT, Chandigarh. Booths were selected by stratified random sampling technique. The status of cold chain equipments was assessed at headquarter of IPPI, 6 regional (distribution) centres, 20 IPPI posts and 5 house to house teams. The cold chain sickness rate was found to be 9.7% in January, 2002. There were reports of breakdown of cold chain maintenance due to defective plugs and sockets, faults in thermostat, leakage of gas. But all vaccine samples picked up randomly were reported potent, as per the test reports provided by Central Research Institute (CRI), Kasauli during the period of study. Temperature charting and cold chain maintenance was found satisfactory, but necessity of improvement, specially regarding the handling of vaccines by the female health worker. Lids of vaccine carriers not closed tightly, frequent opening of lids during immunization, direct exposure of vaccine to atmospheric temperature, keeping the vaccine vial in hand or pocket. More emphasis is to be given on maintenance of cold chain system in orientation training programme of all Health functionaries before the Intensified Pulse Polio Immunization (IPPI) programme.


A simple method for the alpha-oxygenation of aldehydes.
A mild, efficient and general method for the chemospecific alpha-oxygenation of aldehydes is described. Treatment of a series of aldehydes with N-tert-butyl-O-benzoyl hydroxylamine hydrochloride gives the corresponding alpha-oxygenated carbonyl via a proposed pericyclic rearrangement process.


Autochthonous dissolved organic matter potentially fuels methane ebullition from experimental lakes.
Shallow lakes are hotspots for carbon processing and important natural sources of methane (CH4) emission. Ebullitive CH4 flux may constitute the overwhelming majority of total CH4 flux, but the episodic nature of ebullition events makes determining both quantity and the controlling factors challenging. Here we used the world's longest running shallow-lake mesocosm facility, where the experimental treatments are low and high nutrients crossed with three temperatures, to investigate the quantity and drivers of CH4 ebullition. The mean CH4 ebullition flux in the high nutrient treatment (41.5 ± 52.3 mg CH4-C m-2 d-1) mesocosms was significantly larger than in the low nutrient treatment (3.6 ± 5.4 mg CH4-C m-2 d-1) mesocosms, varying with temperature scenarios. Over eight weeks from June to August covered here warming resulted in a weak, but insignificant enhancement of CH4 ebullition. We found significant positive relationships between ebullition and chlorophyll-a, dissolved organic carbon (DOC), biodegradable DOC, δ2H, δ18O and δ13C-DOC, autochthonous dissolved organic matter (DOM) fluorescent components, and a fraction of lipids, proteins, and lignins revealed using ultrahigh-resolution mass spectrometry, and a negative relationship between ebullitive CH4 flux and the percentage volume inhabited of macrophytes. A 24 h laboratory bio-incubation experiment performed at room temperature (20 ± 2 °C) in the dark further revealed a rapid depletion of algal-DOM concurrent with a massive increased CH4 production, whereas soil-derived DOM had a limited effect on CH4 production. We conclude that eutrophication likely induced the loss of macrophytes and increase in algal biomass, and the resultant accumulation algal derived bio-labile DOM potentially drives enhanced outgassing of ebullitive CH4 from the shallow-lake mesocosms.


Information technology.
The AAAS Annual Meeting will be held in Detroit on 26-31 May 1983. The inclusive dates were given incorrectly as 21-31 May in the heading of the Preliminary Program (25 Feb., p. 948). The large body of water shown to the south of Detroit on the cover of the issue of 25 February is Lake Erie. The cover legend stated incorrectly that it was Lake Huron.


The neutrophil-to-lymphocyte ratio in salivary gland cancers treated with pembrolizumab.
A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response prediction. Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6-month progression-free survival (PFS) and secondary outcome of 2-year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed. Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6-month PFS (HR 1.30, 95% CI 1.10-1.54, p = 0.002) and 2-year OS (HR 1.33, 95% CI 1.07-1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17-76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67-75.77, p = 0.013). Higher pretreatment NLR was independently associated with inferior 6-month PFS and 2-year OS in pembrolizumab-treated R/M SGC patients.


Is robotic parathyroidectomy a feasible and safe alternative to targeted open parathyroidectomy for the treatment of primary hyperparathyroidism?
A best evidence topic was written according to a structured protocol. The question addressed was whether robotic parathyroidectomy (RP) is a feasible and safe alternative to targeted open parathyroidectomy for the treatment of primary hyperparathyroidism (pHPT). A total of 36 papers were identified using the reported searches of which 5 represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Targeted parathyroidectomy constitutes the co-gold-standard procedure for pHPT with results equivalent to bilateral cervical exploration. This has led to the proliferation of minimally invasive parathyroidectomy (MIP) techniques for pre-operatively localised adenomas. None has been shown to be overwhelmingly superior. RP constitutes the most recent addition. RP overcomes the limitations of conventional endoscopic surgery and simultaneously avoids a neck scar by concealing it in the axilla or infraclavicular area. The evidence from the present review shows that RP is feasible and leads to a superior cosmetic result compared to targeted open parathyroidectomy (TOP) with an equivalent safety profile. As with every surgical technique, appropriate patient selection is crucial. Long-term data are currently awaited on RP especially in view of its high cost and long operative time compared to TOP and other MIP techniques. Hence, RP offers a viable but costly alternative to other forms of MIP in patients where even the smallest and most cosmetic neck scar is not an option.


Poor motor function is associated with reduced sensory processing after stroke.
The possibility to regain motor function after stroke depends on the intactness of motor and sensory pathways. In this study, we evaluated afferent sensory pathway information transfer and processing after stroke with the coherence between cortical activity and a position perturbation (position-cortical coherence, PCC). Eleven subacute stroke survivors participated in this study. Subjects performed a motor task with the affected and non-affected arm while continuous wrist position perturbations were applied. Cortical activity was measured using EEG. PCC was calculated between position perturbation and EEG at the contralateral and ipsilateral sensorimotor area. The presence of PCC was quantified as the number of frequencies where PCC is larger than zero across the sensorimotor area. All subjects showed significant contralateral PCC in affected and non-affected wrist tasks. Subjects with poor motor function had a reduced presence of contralateral PCC compared with subjects with good motor function in the affected wrist tasks. Amplitude of significant PCC did not differ between subjects with good and poor motor function. Our results show that poor motor function is associated with reduced sensory pathway information transfer and processing in subacute stroke subjects. Position-cortical coherence may provide additional insight into mechanisms of recovery of motor function after stroke.


Kandenols A-E, eudesmenes from an endophytic Streptomyces sp. of the mangrove tree Kandelia candel.
Five novel eudesmene-type sesquiterpenes, kandenols A-E (1-5), have been isolated from Streptomyces sp. HKI0595 derived from the mangrove plant Kandelia candel. Their structures were established through NMR and mass spectrometry, and absolute configurations were established by the Mosher method and comparison of CD spectra with α-rotunol and β-rotunol. The kandenols are reminiscent of various plant-derived eudesmenes, yet kandenols B and C are unusual because of their hydroperoxide moieties. Kandenol E is the first bacterial agarofuran, which belongs to an important group of antibiotics. Whereas the kandenols display no cytotoxicity against 12 human cell lines, weak to moderate antimicrobial activities were detected against Bacillus subtilis ATCC 6633 and Mycobacterium vaccae IMET 10670.


Adsorption and separation of amyloid beta aggregates using ferromagnetic nanoparticles coated with charged polymer brushes.
Amyloid beta (Aβ) protein aggregates, which include fibrils and oligomers, are neurotoxic and are considered to cause Alzheimer's disease. Thus, separation of these Aβ aggregates from biological samples is important. Herein, we report the use of strongly ferromagnetic few-layer graphene-coated magnetic nanoparticles (C/Co), which were functionalized with a cationic polymer, poly[3-(methacryloyl amino)propyl]trimethylammonium chloride (polyMAPTAC), C/Co@polyMAPTAC, for the adsorption and magnetic separation of Aβ aggregates. Fast adsorption (∼1 min) of Aβ fibrils and oligomers onto the particles was observed. Interestingly, the Aβ monomer was not captured by the particles, suggesting that binding to Aβ molecules is toxic species-selective. Selective adsorption was also observed in the presence of serum albumin protein. We also showed that C/Co@polyMAPTAC could reduce the cytotoxicity of the Aβ aggregate solutions. This study should be useful for further elucidation of the application of nanoparticle adsorption in mediating Aβ toxicity.


Directional Freezing of Nanocellulose Dispersions Aligns the Rod-Like Particles and Produces Low-Density and Robust Particle Networks.
We show that unidirectional freezing of nanocellulose dispersions produces cellular foams with high alignment of the rod-like nanoparticles in the freezing direction. Quantification of the alignment in the long direction of the tubular pores with X-ray diffraction shows high orientation of cellulose nanofibrils (CNF) and cellulose nanocrystals (CNC) at particle concentrations above 0.2 wt % (CNC) and 0.08 wt % (CNF). Aggregation of CNF by pH decrease or addition of salt significantly reduces the particle orientation; in contrast, exceeding the concentration where particles gel by mobility constraints had a relatively small effect on the orientation. The dense nanocellulose network formed by directional freezing was sufficiently strong to resist melting. The formed hydrogels were birefringent and displayed anisotropic laser diffraction patterns, suggesting preserved nanocellulose alignment and cellular structure. Nondirectional freezing of the hydrogels followed by sublimation generates foams with a pore structure and nanocellulose alignment resembling the structure of the initial directional freezing.


Heritability of glomerulonephritis: A Swedish adoption study.
Glomerulonephritis clusters in families. However, infections are common inducers of glomerulonephritis and may also cluster in families. Studies of adoptees and their biological and adoptive parents may disentangle genetic from environmental causes of familial clustering. This is the first adoption study aimed to estimate the genetic contribution to the familial transmission of glomerulonephritis. We performed a family study for Swedish-born adoptees (born 1945-2000) and their biological and adoptive parents. The Swedish Multi-Generation Register was linked to the Hospital Inpatient Register for the period 1964-2012 and the Hospital Outpatient Register for 2001-2012. Odds ratio (OR) for glomerulonephritis was determined for adoptees with a biological parent with glomerulonephritis compared with adoptees without an affected biological parent. Similarly, the OR for glomerulonephritis was also determined in adoptees with an affected adoptive parent compared with adoptees without an affected adoptive parent. Heritability was estimated to be twice the observed tetrachoric correlation among adoptees and biological parents, under the assumption that only additive genetic factors contribute to the similarity between biological parents and adoptees. The OR for glomerulonephritis was 4.08 in adoptees (95% confidence interval [CI] 1.79-9.27, P-value = 0.001) of biological parents diagnosed with glomerulonephritis. The OR for glomerulonephritis was 1.67 in adoptees (95% CI 0.53-5.26, P-value = 0.380) of adoptive parents diagnosed with glomerulonephritis. The heritability was 48%. Family history of glomerulonephritis in a biological parent is a risk factor for glomerulonephritis. The present study indicates that genetic factors play an important role in the aetiology of glomerulonephritis.


Can Wikipedia Be Used to Derive an Open Clinical Terminology?
Clinical terminologies play an essential role in enabling semantic interoperability between medical records. However, existing terminologies have several issues that impact data quality, such as content gaps and slow updates. In this study we explore the suitability of existing, community-driven resources, specifically Wikipedia, as a potential source to bootstrap an open clinical terminology, in terms of content coverage. In order to establish the extent of the coverage, a team of expert clinical terminologists manually mapped a clinically-relevant subset of SNOMED CT to Wikipedia articles. The results show that approximately 80% of the concepts are covered by Wikipedia. Most concepts that do not have a direct match in Wikipedia are composable from multiple articles. These findings are encouraging and suggest that it should be possible to bootstrap an open clinical terminology from Wikipedia.


Promoting a Significant Increase in the Photoluminescence Quantum Yield of Terbium(III) Complexes by Ligand Modification.
Two discrete mononuclear complexes, [Tb(bbpen)(NO3)] (I) and [Tb(bbppn)(NO3)] (II), for which H2bbpen = N,N'-bis(2-hydroxybenzyl)-N,N'-bis(pyridin-2-ylmethyl)ethylenediamine and H2bbppn = N,N'-bis(2-hydroxylbenzyl)-N,N'-bis(pyridin-2-ylmethyl)-1,2-propanediamine, were synthesized and characterized by FTIR, Raman, and photoluminescence (PL, steady-state and time-resolved modes) spectroscopy. The attachment of a methyl group to the ethylenediamine portion of the ligand backbone differentiates II from I and acts as a determining feature to both the structural and optical properties of the former. The single-crystal X-ray structure of H2bbppn is described here for the first time, while that of complex II has been redetermined in the monoclinic C2 space group in light of new diffraction data. In II, selective crystallization leads to spontaneous resolution of enantiomeric molecules in different crystals. Absolute emission quantum yields (ϕ) and luminescence excited-state lifetimes (at room temperature and 11 K) were measured for both complexes. Despite their similar molecular structures, I and II exhibit remarkably different ϕ values of 21 ± 2% and 67 ± 7%, respectively, under UV excitation at room temperature. Results of quantum-mechanical (DFT and TD-DFT) calculations and experimental PL measurements also performed for H2bbpen and H2bbppn confirmed that both ligands are suitable to work as "antennas" for TbIII. Considering the 5D4 lifetime profiles and the significantly higher absolute quantum yield of II, it appears that thermally active nonradiative pathways present in I are minimized in II due to differences in the conformation of the ethylenediamine bridge.


Calcium-alginate coated, whey protein-based microspheres: preparation, some properties and opportunities.
An 'all aqueous' encapsulation process followed by a heat treatment was used to prepare calcium-alginate-coated, whey protein-based, water insoluble microspheres containing micronized calcium carbonate as a model core. Results obtained with this process were compared to those obtained with a similar process in which chemical cross-linking was utilized. At an initial core load of 25 or 50% (w/w), core retention ranged from 84.2-95.12% and was not significantly affected by the initial core load or by the cross-linking method. Regardless of the cross-linking method, protein retention during the process was high and ranged from 78.2-87.5%. Outer topography of the microspheres was not influenced by the cross-linking method, however, at a given composition, the inner structure of heat treated microspheres differed from that obtained with chemically-cross-linked microspheres. Swelling properties of denovo microspheres were affected by pH. Results indicated that the micronized calcium carbonate could be used as a porogenic core. Removal of the core, by an acid treatment, allowed preparing microporous delivery devices. In addition to offer opportunities for encapsulation and delivery of crystalline core, the investigated process can provide means to prepare 'ghost' microporous delivery systems that can, in potential, be loaded, following their preparation, with sensitive core materials at conditions that favour the stability and functionality of this core.


Changes in weight at the end of life: characterizing weight loss by time to death in a cohort study of older men.
The purpose of this analysis was to characterize the natural history of weight change in the years prior to death among older persons and to examine how this pattern varies according to longevity and cause of death. Weight trajectories were analyzed by using data from 800 male decedents from the Baltimore Longitudinal Study of Aging (Maryland, 1958-2005) observed beginning an average of 19 years before death. A model including 3 distinct periods of weight change (weight stability/gain, mild weight loss, and accelerated weight loss before death) provided the best fit for all age-at-death groups. Approximately 9 years before death, the rate of weight loss increased to an average of 0.39 kg/year (P < 0.001) for all-cause mortality. For cancer deaths, weight loss accelerated significantly 3 years before death, regardless of age group. For cardiovascular deaths, the best-fitting inflection point increased with age, from 5 years for participants aged 60-69 years to 9-10 years before death for those aged 80 years or older. Results suggest that weight loss in older persons may begin earlier than previously believed. The duration of weight loss for noncancer deaths suggests that even distal changes in energy balance may be linked to risk of death.


Diabetes research. Islet transplants not yet ready for prime time.
When researchers in Edmonton, Canada, announced last month that a new procedure for transplanting pancreatic islet cells had freed seven adults with type I diabetes from taking insulin, the results generated a great deal of public enthusiasm. Some important caveats tended to get lost, however. One drawback is that transplant recipients would need to take immunosuppressive drugs for the rest of their lives to keep from rejecting the tissue. But more importantly, even if the benefits of the transplants outweigh the risks of the drugs, there's just not enough islet tissue to go around and there won't be anytime soon.


Dual Antiplatelet Therapy or Antiplatelet Plus Anticoagulant Therapy in Patients with Peripheral and Chronic Coronary Artery Disease: An Updated Review.
Despite evidence-based therapies, patients presenting with atherosclerosis involving more than one vascular bed, such as those with peripheral artery disease (PAD) and concomitant coronary artery disease (CAD), constitute a particularly vulnerable group characterized by enhanced residual long-term risk for major adverse cardiac events (MACE), as well as major adverse limb events (MALE). The latter are progressively emerging as a difficult outcome to target, being correlated with increased mortality. Antithrombotic therapy is the mainstay of secondary prevention in both patients with PAD or CAD; however, the optimal intensity of such therapy is still a topic of debate, particularly in the post-acute and long-term setting. Recent well-powered randomized clinical trials (RCTs) have provided data in favor of a more intense antithrombotic therapy, such as prolonged dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor or a therapy with aspirin combined with an anticoagulant drug. Both approaches increase bleeding and selection of patients is a key issue. The aim of this review is, therefore, to discuss and summarize the most up-to-date available evidence for different strategies of anti-thrombotic therapies in patients with chronic PAD and CAD, particularly focusing on studies enrolling patients with both types of atherosclerotic disease and comparing a higher- versus a lower-intensity antithrombotic strategy. The final objective is to identify the optimal tailored approach in this setting, to achieve the greatest cardiovascular benefit and improve precision medicine.


Comparative effects of beta-propiolactone on mice, mouse-derived cell cultures, and Venezuelan equine encephalomyelitis virus.
Studies were made comparing the toxicity of beta-propiolactone (BPL) for mammalian (mouse) cells in vitro and for mice and for Venezuelan equine encephalomyelitis (VEE) virus which is highly cytopathogenic for each. The mammalian cells grown in tissue culture were found to be adversely affected by BPL in concentrations ranging from 0.001 to 0.1 mg/ml of supernatant fluid. The difference in response was influenced by the menstruum in which the BPL was suspended and the difference in cell types tested. Tenfold less BPL appeared to be required to destroy the cells when it was suspended in a balanced salt solution than when it was suspended in protein-containing solutions such as beef heart infusion broth or medium 199 plus 20% horse serum. Secondary embryonic mouse lung cells seemed slightly more adversely affected by BPL than the established embryonic lung or L cells. BPL given to mice by intranasal instillation and by intracerebral injection was lethal to half of the animals within 2 days at doses of 0.31 and 0.39 mg, respectively. Higher concentrations of BPL were required to rapidly inactivate the virus in vitro than were required to kill mice or to cause a toxic effect on cells in culture. It required 10 mg/ml of BPL to completely inactivate a high-titered VEE virus preparation in 5 min and 1 mg/ml to inactivate most, but not all, of the virus in 15 min. A concentration of 0.1 mg/ml of BPL had only a slight effect on the virus after a period as long as 60 min. Evidence is presented indicating that simultaneous inactivation of all of the properties of the VEE virus particles by BPL aerosols did not occur at the same time but that, after treatment, the virus possessed a limited ability to immunize mice despite a loss in infectivity.