Valdecoxib (Pharmacia).
Pharmacia (formerly Searle), in collaboration with Pfizer and Yamanouchi, has developed valdecoxib, a second-generation cyclooxygenase (COX)-2 inhibitor as a follow-up to celecoxib, for the treatment of arthritis. Pharmacia filed an NDA with the FDA in March 2001 for the treatment of acute pain, dysmenorrhea, osteoarthritis (OA) and rheumatoid arthritis (RA). At this time, Pharmacia anticipated a 12-month review [402883]. In June 2001, launch was anticipated in 2002 [412616], and in November 2001, valdecoxib was granted FDA approval [429715]. The company claims that valdecoxib has improved potency and broader therapeutic range than other COX-2 inhibitors including celecoxib, and has the potential for once-daily dosing [287279], [313957]. By 1999, due to the poor water solubility of valdecoxib, Searle was also developing the prodrug parecoxib [324667]. Valdecoxib has been described by Searle as almost superimposable at the site critical for COX-2 inhibition, a structural side pocket in the enzyme which coincides with the sulfonamide group of the drug [324667]. In April 2000, Morgan Stanley Dean Witter estimated sales would be US $400 million in 2003, rising to US $750 million in 2004 [375906]. In April 2001, Merrill Lynch predicted world sales of US $460 million in 2002, rising to $1,065 million in 2005 [420574]. In September 2000, Merrill Lynch reported that additional pain data were being accumulated for this drug, the possible inclusion of which could push filing back to later in the first half of 2001 [382577]. In May 2001, Merrill Lynch expected launch in 2002 [411811]. In August 2001, Lehman Brothers predicted that launch would take place in thefirst half of 2002 and the product would make peak sales of US $1,500 million [420809]. Credit Suisse predicted in this month that total sales would reach US $330 million in 2002, rising to US $1832 million in 2004 [422318]. In September 2001, Morgan Stanley expected launch in the first half of 2002 [427113]. By October 2001, Credit Suisse had revised its sales predictions to US $180 million in 2002, US $790 million in 2003 and US $1,430 in 2004 [427185].


Supramolecular Arrangement of Lignosulfonate-Based Iron Heteromolecular Complexes and Consequences of Their Interaction with Ca2+ at Alkaline pH and Fe Plant Root Uptake Mechanisms.
Previous studies have shown that natural heteromolecular complexes might be an alternative to synthetic chelates to correct iron (Fe) deficiency. To investigate the mechanism of action of these complexes, we have studied their interaction with Ca2+ at alkaline pH, Fe-binding stability, Fe-root uptake in cucumber, and chemical structure using molecular modeling. The results show that a heteromolecular Fe complex including citric acid and lignosulfonate as binding ligands (Ls-Cit) forms a supramolecular system in solution with iron citrate interacting with the hydrophobic inner core of the lignosulfonate system. These structural features are associated with high stability against Ca2+ at basic pH. Likewise, unlike Fe-EDDHA, root Fe uptake from Ls-Cit implies the activation of the main root responses under Fe deficiency at the transcriptional level but not at the post-transcriptional level. These results are consistent with the involvement of some plant responses to Fe deficiency in the plant assimilation of complexed Fe in Ls-Cit under field conditions.


Pulmonary artery smooth muscle cells from normal subjects and IPAH patients show divergent cAMP-mediated effects on TRPC expression and capacitative Ca2+ entry.
Pulmonary vascular remodeling due to overgrowth of pulmonary artery smooth muscle cells (PASMC) is a major cause for the elevated vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased cytosolic Ca(2+) concentration, resulting from enhanced capacitative Ca(2+) entry (CCE) and upregulated transient receptor potential (TRP) channel expression, is involved in stimulating PASMC proliferation. The current study was designed to determine the impact of cAMP, a second messenger that we hypothesized would blunt aspects of PASMC activity, as a possible contributor to IPAH pathophysiology. Short-term (30 min) pretreatment with forskolin (FSK; 10 muM), a direct activator of adenylyl cyclase, in combination with the cyclic nucleotide phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 200 muM), attenuated CCE in PASMC from normal subjects, patients without pulmonary hypertension (NPH), and patients with IPAH. The FSK-mediated CCE inhibition was independent of protein kinase A (PKA), because the PKA inhibitor H89 negligibly affected the decrease in CCE produced by cAMP. By contrast, longer (4 h) treatment with FSK (with IBMX) attenuated CCE in normal and NPH PASMC but enhanced CCE in IPAH PASMC. This enhancement of CCE was abolished by PKA inhibition and associated with an upregulation of TRPC3. In addition, cAMP increased TRPC1 mRNA expression in IPAH (but not in normal or NPH) PASMC, an effect blunted by H89. Furthermore, iloprost, a prostacyclin analog that increases cAMP, downregulated TRPC3 expression in IPAH PASMC and FSK-mediated cAMP increase inhibited IPAH PASMC proliferation. Although a rapid rise in cellular cAMP decreases CCE by a PKA-independent mechanism, sustained cAMP increase inhibits CCE in normal and NPH PASMC but increases CCE via a PKA-dependent pathway in IPAH PASMC. The divergent effect of cAMP on CCE parallels effects on TRPC expression. The results suggest that the combined use of a PKA inhibitor and cAMP-elevating drugs may provide a novel approach for treatment of IPAH.


Intra-operative tube stenting, palliation for jaundice in carcinoma gall bladder.
Majority of patients with advanced carcinoma gall bladder have irresectable disease and require palliation for jaundice, pruritus and cholangitis. These cases presenting with jaundice are usually high risk cases to undergo any major surgical procedure like segment-III hepaticodochojejunostomy. So intra-operative tube stenting was attempted in 6 patients of carcinoma gall bladder but technically, it was possible in 4 cases only. In 2 cases because of massive locoregional disease it was not possible to cannulate the proximal part of the bile duct. The distal end of the tube was passed either in the duodenum or proximal part of the jejunum. Patients were followed up, showed good recovery from jaundice and pruritus.


Regulation of major histocompatibility complex class II gene expression in trophoblast cells.
Trophoblast cells are unique because they are one of the few mammalian cell types that do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to IFN-gamma. The absence of MHC class II antigen expression on trophoblast cells has been postulated to be one of the essential mechanisms by which the semi-allogeneic fetus evades immune rejection reactions by the maternal immune system. Consistent with this hypothesis, trophoblast cells from the placentas of women suffering from chronic inflammation of unknown etiology and spontaneous recurrent miscarriages have been reported to aberrantly express MHC class II antigens. The lack of MHC class II antigen expression on trophoblast cells is due to silencing of expression of the class II transactivator (CIITA), a transacting factor that is essential for constitutive and IFN-gamma-inducible MHC class II gene transcription. Transfection of trophoblast cells with CIITA expression vectors activates both MHC class II and class Ia antigen expression, which confers on trophoblast cells both the ability to activate helper T cells, and sensitivity to lysis by cytotoxic T lymphocytes. Collectively, these studies strongly suggest that stringent silencing of CIITA (and therefore MHC class II) gene expression in trophoblast cells is critical for the prevention of immune rejection responses against the fetus by the maternal immune system. The focus of this review is to summarize studies examining the novel mechanisms by which CIITA is silenced in trophoblast cells. The elucidation of the silencing of CIITA in trophoblast cells may shed light on how the semi-allogeneic fetus evades immune rejection by the maternal immune system during pregnancy.


[Applicability of molecular electrostatic interaction models to describing ionic strength dependence of reaction rate between myoglobin and cytochrome c].
The nonlinear regression method was used for the evaluation of applicability of the known model equations (Wherland-Gray, Brönsted-Debay-Hukkel and "parallel disks") which describe the ionic strength dependence of the reaction rate between charged molecules to the redox reaction of cytochrome c with sperm whale myoglobin modified at His 12(A10) with the bromoacetate spin label, and pig myoglobin. Unlike the native sperm whale Mb studied earlier [1], the objects chosen have monotonous pH-dependence of the reaction rate and are more simple with regards to electrostatic interactions in the electron-transfer complex. This allowed to study the influence of the total as well as the local protein charge on the correspondence of the ion strength dependencies to the theoretical models and optimal parameters of the equations. It was shown that the models considered, as in the case of the native sperm whale Mb-Cyt c reaction, permit satisfactory description of the experimental data, but the obtained parameters cannot be applied to the whole proteins or their contact sites. In the best case (Wherland-Gray equation) it is possible to do if the distribution of electrostatic potential in the contact area is considered. The reason can be that, unlike other protein redox-systems, the contact sites of both Mb and Cyt c have the charged residues of both signs, and the His GH1 residue located in the contact Mb site is not only involved in the electrostatic interactions in electron-transfer complex, but also participates directly in the mechanism of charge transfer.


Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram.
Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT-RR combinations. Systematic review. We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett's correction). We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), respectively. The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.


Current Trends in Fabrication of Biomaterials for Bone and Cartilage Regeneration: Materials Modifications and Biophysical Stimulations.
The aim of engineering of biomaterials is to fabricate implantable biocompatible scaffold that would accelerate regeneration of the tissue and ideally protect the wound against biodevice-related infections, which may cause prolonged inflammation and biomaterial failure. To obtain antimicrobial and highly biocompatible scaffolds promoting cell adhesion and growth, materials scientists are still searching for novel modifications of biomaterials. This review presents current trends in the field of engineering of biomaterials concerning application of various modifications and biophysical stimulation of scaffolds to obtain implants allowing for fast regeneration process of bone and cartilage as well as providing long-lasting antimicrobial protection at the site of injury. The article describes metal ion and plasma modifications of biomaterials as well as post-surgery external stimulations of implants with ultrasound and magnetic field, providing accelerated regeneration process. Finally, the review summarizes recent findings concerning the use of piezoelectric biomaterials in regenerative medicine.


A structural model of the human serotonin transporter in an outward-occluded state.
The human serotonin transporter hSERT facilitates the reuptake of its endogenous substrate serotonin from the synaptic cleft into presynaptic neurons after signaling. Reuptake regulates the availability of this neurotransmitter and therefore hSERT plays an important role in balancing human mood conditions. In 2016, the first 3D structures of this membrane transporter were reported in an inhibitor-bound, outward-open conformation. These structures revealed valuable information about interactions of hSERT with antidepressant drugs. Nevertheless, the question remains how serotonin facilitates the specific conformational changes that open and close pathways from the synapse and to the cytoplasm as required for transport. Here, we present a serotonin-bound homology model of hSERT in an outward-occluded state, a key intermediate in the physiological cycle, in which the interactions with the substrate are likely to be optimal. Our approach uses two template structures and includes careful refinement and comprehensive computational validation. According to microsecond-long molecular dynamics simulations, this model exhibits interactions between the gating residues in the extracellular pathway, and these interactions differ from those in an outward-open conformation of hSERT bound to serotonin. Moreover, we predict several features of this state by monitoring the intracellular gating residues, the extent of hydration, and, most importantly, protein-ligand interactions in the central binding site. The results illustrate common and distinct characteristics of these two transporter states and provide a starting point for future investigations of the transport mechanism in hSERT.


Pyridoxine-dependent seizures associated with hypophosphatasia in a newborn.
Pyridoxine dependency and congenital hypophosphatasia are unusual metabolic disorders. We report a female infant born from healthy consanguineous parents with shortening of limbs, detected during pregnancy by ultrasonography. Immediately after delivery, the baby was admitted to the neonatal intensive care unit because of respiratory distress. A bone radiograph showed hypomineralization of all bones, and serum alkaline phosphatase was very low (10 U/L). Within the first day of life, seizures (focal clonic and tonic) started. The seizures were refractory to phenobarbital and other antiepileptic drugs. The first electroencephalogram (EEG) showed a burst-suppression pattern. Pyridoxine was administered (50 mg/kg) and completely controlled the seizures. Antiepileptic drugs were discontinued, and a maintenance dose of pyridoxine (10 mg/day) was established. A postpyridoxine EEG revealed the disappearance of the burst-suppression pattern. The patient died at age 26 days. Pyridoxine-dependent seizures, when recognized early and treated, have a more favorable prognosis. However, hypophosphatasia detected at birth almost always has a lethal outcome.


Diagnosis and rehabilitation of deep wound infection and internal fixation rejection in elbow: A case report.
This study aims at diagnosis and rehabilitation of a rare case of deep wound infection and internal fixation rejection in elbow. The patient sustained a distal fracture in the humerus 1 year ago, which was internal fixed. The wound always effused and the elbow had pain and swelling; joint motion was limited. Blood sedimentation rate and C reactive protein level increased, bacterial culture suggested deep wound infection, and ultrasound indicated inflammation. The main diagnoses were deep wound infection and internal fixation rejection. Therapeutics interventions were antibiotic agents, physical therapy, operative debridement, incision, drainage, and exercise and physical therapy. One year later, the internal fixation was taken out. His elbow was fully mobilized and the fracture healed. He got back to his former job. When encountered deep wound infection again and again after internal fixation, rejection should be considered. Except for anti-infection treatment, rehabilitation cannot be neglected, or the healing process may be delayed.


[Salutogenesis--the extension of physician's capabilities].
Changes in medicine are not only technical but are also relating to people's awareness. The biomedical model is not sufficient to explain the various phenomena and processes of health and disease. Actually the most popular is the holistic approach. In the salutogenesis model, the essential issue is not the disease but the health. In this approach, among numerous variables, the most important is the sense of coherence (SOC) - the personal variability, the key to health. The psychological problems which are essential in Antonovsky's theory, refer to the physicians. Many of the contemporary researches refere to the medicine and psychology. The salutogenesis can be used in medicine as the extension of doctor's and patient's capabilities but not instead of medicine.


Invited review: Neuropathology of tauopathies: principles and practice.
Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance.


Mytilus trossulus in Northern Europe.
From data on allozyme, nuclear DNA and mitochondrial DNA markers, we show that the originally North Pacific/Northwest Atlantic mussel Mytilus trossulus is widespread on North European coasts, earliM. trossuluser thought to be inhabited only by Mytilus edulis. Several local occurrences of , interspersed with a dominant M. edulis, were recorded on the North Sea, Norwegian Sea and Barents Sea coasts of Norway and the Barents and White Sea coasts of Kola Peninsula in Russia. The proportion of M. trossulus genetic background observed at any one site varied from 0 to 95%. These new occurrences are not related to the previously known, introgressed M. trossulus population that occupies the Baltic Sea. The new northern occurrences retain both the F and M M. trossulus mitochondria, which have been lost from the Baltic stock. While hybridization takes place wherever M. trossulus and M. edulis meet, the extent of hybrization varies between the different contact areas. Hybrids are rare, and the hybrid zones are bimodal in the northern areas; more interbreeding has taken place further south in Norway, but even there genotypic disequilibria are higher than those in the steep transition zone between the Baltic mussel and M. edulis: there is no evidence of a collapse toward a hybrid swarm unlike in the Baltic. The Barents and White Sea M. trossulus are genetically slightly closer to the NW Atlantic than NE Pacific populations, while the Baltic mussel has unique features distinguishing it from the others. We postulate that the presence of M. trossulus in Northern Europe is a result of repeated independent inter- or transoceanic cryptic invasions of various ages, up to recent times.


Selected organ dose conversion coefficients for external photons calculated using ICRP adult voxel phantoms and Monte Carlo code FLUKA.
The adult reference male and female computational voxel phantoms recommended by ICRP are adapted into the Monte Carlo transport code FLUKA. The FLUKA code is then utilised for computation of dose conversion coefficients (DCCs) expressed in absorbed dose per air kerma free-in-air for colon, lungs, stomach wall, breast, gonads, urinary bladder, oesophagus, liver and thyroid due to a broad parallel beam of mono-energetic photons impinging in anterior-posterior and posterior-anterior directions in the energy range of 15 keV-10 MeV. The computed DCCs of colon, lungs, stomach wall and breast are found to be in good agreement with the results published in ICRP publication 110. The present work thus validates the use of FLUKA code in computation of organ DCCs for photons using ICRP adult voxel phantoms. Further, the DCCs for gonads, urinary bladder, oesophagus, liver and thyroid are evaluated and compared with results published in ICRP 74 in the above-mentioned energy range and geometries. Significant differences in DCCs are observed for breast, testis and thyroid above 1 MeV, and for most of the organs at energies below 60 keV in comparison with the results published in ICRP 74. The DCCs of female voxel phantom were found to be higher in comparison with male phantom for almost all organs in both the geometries.


Pyrazolopyrimidine-2,4-dione sulfonamides: novel and selective calcitonin inducers.
A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.


Fatal inhalational isopropyl alcohol poisoning in a neonate.
A 37 weeks gestation, 1500 gram male infant with multiple dysmorphic features underwent surgery for gastroschisis several hours after birth. During post-operative mechanical ventilation, 70% isopropyl alcohol was accidentally placed in the humidifier of the ventilator, resulting in an estimated 2 h exposure. While the baby seemed clinically stable, initial neurological examination was confounded by recent sedation and pancuronium paralysis. Initial post-operative hypotension was corrected with fluid administration and remained stable for the remainder of the clinical course. By 2 h post-exposure, he was moving, breathing spontaneously and opening his eyes. Isopropyl alcohol and acetone levels at 1, 6, 10 h post exposure were 31/10, 22/15, 15/20 mmol/L respectively. Isopropyl alcohol elimination t1/2 was 9.6 h. Dialysis or exchange transfusion were considered but due to their high risk and the stable infant condition, it was elected to continue with supportive care only. 12.5 h post-exposure, he suddenly became cyanotic, bradycardic, then asystolic. Resuscitation efforts were unsuccessful. To our knowledge, this is the youngest patient reported to have toxic inhalational exposure to isopropyl alcohol and the first report on isopropyl alcohol pharmacokinetics at this age.


Attributable risk for symptomatic liver cirrhosis in Italy. Collaborative Groups for the Study of Liver Diseases in Italy.
Knowledge of the proportion of liver cirrhosis attributable to the main risk factors is largely based on methodologically questionable clinical reports. The proportion of newly diagnosed cases of symptomatic liver cirrhosis attributable to known risk factors was estimated by a case-control study performed during 1989-1996 in 23 medical divisions of several hospitals distributed throughout Italy. Cases were 462 inpatients with cirrhosis admitted for the first time for liver decompensation. Controls were 651 patients admitted during the same period and to the same hospitals as the cases, for acute diseases unrelated to alcohol and virus infection. The proportion of symptomatic liver cirrhosis cases due to alcohol intake and hepatitis B and C viruses and the combination of these was expressed as the population attributable risk. Attributable risks were 67.9% (95% confidence interval (CI): 53.8-79.4) for alcohol, 40.1% (95% CI: 35.3-45.2) for hepatitis C virus and 4.4% (95% CI: 2.5-7.6) for hepatitis B virus. The three factors together explained 98.1% (95% CI: 81.6-99.6) of cases in men and 67.0% (95% CI: 50.4-85.8) in women. Alcohol is the risk factor with the highest impact on symptomatic liver cirrhosis risk in Italy. From a public health viewpoint, with the elimination of the well-known risk factors (particularly alcohol and hepatitis C virus), liver cirrhosis should become a rare disease.


Emergence of ertapenem resistance in an Escherichia coli clinical isolate producing extended-spectrum beta-lactamase AmpC.
Escherichia coli isolate MEV, responsible for a bloodstream infection, was resistant to penicillins, cephalosporins, and ertapenem. Molecular and biochemical characterization revealed the production of a novel, chromosome-borne, extended-spectrum AmpC (ESAC) β-lactamase with a Ser-282 duplication and increased carbapenemase activity. This study demonstrates for the first time that chromosome-borne ESAC β-lactamases can contribute to the emergence of ertapenem resistance in E. coli clinical isolates.


Tumor dimension and prognosis in surgically treated lung cancer: for intentional limited resection.
Tumors with a maximum dimension of 3 cm are categorized as T1, whereas those greater than 3 cm are T2 by TNM classification. Some physicians suggest that early-stage peripheral lung cancer should have a maximum tumor diameter of 2 cm and that limited surgery (segmentectomy without lymph node dissection) is acceptable for the patients. In this study, the relationship between the tumor dimension and prognosis was analyzed in 207 patients with surgically treated primary non-small-cell lung cancer (SCLC). The 5-year survival rate of those with tumors 3 cm or less and without lymph node (LN) metastases was 86%, which was significantly higher than that of those with tumors more than 3 cm and without hilar and mediastinal LN metastases (65%) (p < 0.05). However, 33% of the patients with tumors 3 cm or less had LN metastases, and the 5-year survival rate did not differ between those with tumors 3 cm or less (60%) and those with tumors more than 3 cm (54%). Twenty-eight percent of patients with tumors 2 cm or less had LN metastases, and the 5-year survival rate of the patients with tumors 2 cm or less was 62%. The 5-year survival rate of those with tumors 2 cm or less and without LN metastases was 88%. Forty-six patients with tumors 2 cm or less included 5 cases with an intrapulmonary metastasis in the same lobe (11%). In conclusion, a size of 3 cm is an appropriate boundary as the T factor. Because those with tumors 2 cm or less have a relatively high percentage of LN metastases, intraoperative frozen sections of LN should be considered for those undergoing limited surgery for primary non-SCLCs 2 cm or less. Intrapulmonary metastases also should be considered for those undergoing limited surgery even if the maximum dimension of the primary tumor is less than 2 cm.


Catalytic Reductive Alcohol Etherifications with Carbonyl-Based Compounds or CO2 and Related Transformations for the Synthesis of Ether Derivatives.
Ether derivatives have myriad applications in several areas of chemical industry and academia. Hence, the development of more effective and sustainable protocols for their production is highly desired. Among the different methodologies reported for ether synthesis, catalytic reductive alcohol etherifications with carbonyl-based moieties (aldehydes/ketones and carboxylic acid derivatives) have emerged in the last years as a potential tool. These processes constitute appealing routes for the selective production of both symmetrical and asymmetrical ethers (including O-heterocycles) with an increased molecular complexity. Likewise, ester-to-ether catalytic reductions and hydrogenative alcohol etherifications with CO2 to dialkoxymethanes and other acetals, albeit in less extent, have undergone important advances, too. In this Review, an update of the recent progresses in the area of catalytic reductive alcohol etherifications using carbonyl-based compounds and CO2 have been described with a special focus on organic synthetic applications and catalyst design. Complementarily, recent progress made in catalytic acetal/ketal-to-ether or ester-to-ether reductions and other related transformations have been also summarized.


Can Kinesiological Activities Change "Pure" Motor Development in Preschool Children during One School Year?
The purpose of this study was to evaluate the effects of an additional, organized, and more intensive kinesiological treatment on "pure" motor abilities in preschool children. In the present study an experimental treatment was carried out on a sample of 37 preschool boys by applying kinesiological activities. The 60 minute treatment was applied over a period of one school year (9 months), twice a week. A control group of 31 boys were trained according to the regular program for preschool institutions. Treatment effects were assessed by 8 motor ability tests and 5 anthropometric measures. The significant differences between the groups, which were observed after the final measurement and compared to the initial one, proved that the kinesiological treatment had a positive impact on the general development of "pure" motor abilities. The most significant effect of experimental kinesiological treatment was the improvement in whole body force, flexibility and coordination of preschool boys. These findings, obtained only in one school year, point to the importance of physical exercise and the application of additional kinesiological activities with various modalities, to improve motor development, even morphological growth and development in preschool children. The effects of the perennial application of kinesiological activities, under the supervision of kinesiological professionals, could be beneficial and could form the basis for a better biological and motor development in older age.


Application of a generalized linear mixed model to analyze mixture toxicity: survival of brown trout affected by copper and zinc.
Increased concerns about the toxicity of chemical mixtures have led to greater emphasis on analyzing the interactions among the mixture components based on observed effects. The authors applied a generalized linear mixed model (GLMM) to analyze survival of brown trout (Salmo trutta) acutely exposed to metal mixtures that contained copper and zinc. Compared with dominant conventional approaches based on an assumption of concentration addition and the concentration of a chemical that causes x% effect (ECx), the GLMM approach has 2 major advantages. First, binary response variables such as survival can be modeled without any transformations, and thus sample size can be taken into consideration. Second, the importance of the chemical interaction can be tested in a simple statistical manner. Through this application, the authors investigated whether the estimated concentration of the 2 metals binding to humic acid, which is assumed to be a proxy of nonspecific biotic ligand sites, provided a better prediction of survival effects than dissolved and free-ion concentrations of metals. The results suggest that the estimated concentration of metals binding to humic acid is a better predictor of survival effects, and thus the metal competition at the ligands could be an important mechanism responsible for effects of metal mixtures. Application of the GLMM (and the generalized linear model) presents an alternative or complementary approach to analyzing mixture toxicity.


CBT and the future of personalized treatment: a proposal.
Over the past several decades, the diagnosis of mental disorders has been characterized by classifying psychopathology into as many discrete diagnoses as can be reliability identified (e.g., APA, 2013). There is increasing evidence, however, that this approach to diagnosis may come at the expense of validity as trivial symptom-level differences are emphasized with little regard for common core mechanisms. Traditionally, cognitive-behavioral (CBT) approaches to treating psychopathology have followed a diagnosis-specific approach such that unique protocols have been developed for most disorders. Recent advances in CBT have suggested that targeting transdiagnostic mechanisms responsible for the development and maintenance of a wider range of psychopathology may be a more efficient approach to treatment than addressing disorder symptoms themselves. In order to create a more personalized treatment package, we propose establishing a profile for each patient that quantifies dysfunction in terms of empirically-supported underlying mechanisms; we further suggest that data from this profile be used to select CBT modules specific to the core mechanisms maintaining an individual patient's symptoms.


Advanced load frequency control of microgrid using a bat algorithm supported by a balloon effect identifier in the presence of photovoltaic power source.
Due to the unpredictability of the majority of green energy sources (GESs), particularly in microgrids (μGs), frequency deviations are unavoidable. These factors include solar irradiance, wind disturbances, and parametric uncertainty, all of which have a substantial impact on the system's frequency. An adaptive load frequency control (LFC) method for power systems is suggested in this paper to mitigate the aforementioned issues. For engineering challenges, soft computing methods like the bat algorithm (BA), where it proves its effectiveness in different applications, consistently produce positive outcomes, so it is used to address the LFC issue. For online gain tuning, an integral controller using an artificial BA is utilized, and this control method is supported by a modification known as the balloon effect (BE) identifier. Stability and robustness of analysis of the suggested BA+BE scheme is investigated. The system with the proposed adaptive frequency controller is evaluated in the case of step/random load demand. In addition, high penetrations of photovoltaic (PV) sources are considered. The standard integral controller and Jaya+BE, two more optimization techniques, have been compared with the suggested BA+BE strategy. According to the results of the MATLAB simulation, the suggested technique (BA+BE) has a significant advantage over other techniques in terms of maintaining frequency stability in the presence of step/random disturbances and PV source. The suggested method successfully keeps the frequency steady over I and Jaya+BE by 61.5% and 31.25%, respectively. In order to validate the MATLAB simulation results, real-time simulation tests are given utilizing a PC and a QUARC pid_e data acquisition card.


Shear bond strength of metal-ceramic repair systems.
When clinical fractures of the ceramic veneer on metal-ceramic prostheses can be repaired, the need for remake may be eliminated or postponed. Many different ceramic repair materials are available, and bond strength data are necessary for predicting the success of a given repair system. This study evaluated the shear bond strength of different repair systems for metal-ceramic restorations applied on metal and porcelain. Fifty cylindrical specimens (9 x 3 mm) were fabricated in a nickel-chromium alloy (Vera Bond II) and 50 in feldspathic porcelain (Noritake). Metal (M) and porcelain (P) specimens were embedded in a polyvinyl chloride (PVC) ring and received 1 of the following bonding and resin composite repair systems (n=10): Clearfil SE Bond/Clearfil AP-X (CL), Bistite II DC/Palfique (BT), CoJet Sand/Z100 (CJ), Scotchbond Multipurpose Plus/Z100 (SB) (control group), or CoJet Sand plus Scotchbond Multipurpose Plus/Z100 (CJSB). The specimens were stored in distilled water for 24 hours at 37 degrees C, thermal cycled (1000 cycles at 5 degrees C to 55 degrees C), and stored at 37 degrees C for 8 days. Shear bond tests between the metal or ceramic specimens and repair systems were performed in a mechanical testing machine with a crosshead speed of 0.5 mm/min. Mean shear bond strength values (MPa) were submitted to 1-way ANOVA and Tukey honestly significant difference tests (alpha=.05). Each specimen was examined under a stereoscopic lens with x30 magnification, and mode of failure was classified as adhesive, cohesive, or a combination. On metal, the mean shear bond strength values for the groups were as follows: MCL, 18.40 +/- 2.88(b); MBT, 8.57 +/- 1.00(d); MCJ, 25.24 +/- 3.46(a); MSB, 16.26 +/- 3.09(bc); and MCJSB, 13.11 +/- 1.24(c). On porcelain, the mean shear bond strength values of each group were as follows: PCL, 16.91 +/- 2.22(b); PBT, 18.04 +/- 3.23(ab); PCJ, 19.54 +/- 3.77(ab); PSB, 21.05 +/- 3.22(a); and PCJSB, 16.18 +/- 1.71(b). Within each substrate, identical superscript letters denote no significant differences among groups. The bond strength for the metal substrate was significantly higher using the CJ system. For porcelain, SB, CJ, and BT systems showed the highest shear bond strength values, and only SB was significantly different compared to CL and CJSB (P<.05). This study suggests that when fracture involves only feldspathic porcelain, any of the evaluated systems may be used, since the fracture occurred on the porcelain substrate and not on the bond interface of porcelain-restorative material. However, for the nickel-chromium alloy tested, the CoJet Sand system showed the best results for repair.


Evaluation of Using Fly Ash as a Weighing Material for Oil-Based Drilling Fluid.
Innovation and sustainability are essential in the fast-changing oil and gas business. Fly ash, a byproduct of coal combustion in power plants and factories, has become a valuable resource in many industries, changing the concept of waste materials. Fly ash is essential to sustainable development and environmental care due to its unique qualities and multiple applications. In the drilling industry, a well-designed drilling fluid is essential and this requires the use of various additives that serve specific functions to achieve a successful borehole. This study investigates the use of fly ash as a weighing material in oil-based mud, with the intent to develop an economically acceptable drilling fluid system using industrial waste. The study compared fly ash to three commonly used weighing materials in the drilling industry: calcium carbonate (CaCO3), barite (BaSO4), and ilmenite (FeTiO3). Drilling fluids were prepared using these weighing materials at various weights, and their properties (density, electrical stability, rheological features, and filtration properties) were measured using API-recommended methods. The rheology and filtration tests were conducted at elevated temperatures (350 °F). The results indicate that fly ash has the potential to be a useful weighing material in drilling operations. It can increase the fluid density up to 10 ppg without affecting the rheological properties at 350 °F. Additionally, the electrical stability of the drilling fluid was enhanced compared to the other used weighing materials. The addition of fly ash also improved rheological characteristics such as plastic viscosity, yield point, and gel strength without affecting HPHT filtration properties. The carrying capacity was improved by 53 and 86% over calcium carbonate and barite, respectively. Overall, the findings suggest that fly ash can be a viable alternative to other weighing materials in the recommended density range.


Human olfactory mucosa in schizophrenia.
Recent evidence indicates that developmental anomalies may underlie some symptoms of schizophrenia, while psychophysical studies have demonstrated olfactory deficits in this disease. The postmortem olfactory mucosa of elderly schizophrenic patients was examined to characterize the molecular phenotype of this tissue. The distribution of developmentally regulated cytoskeletal proteins, a synaptic vesicle protein, a neural marker protein, a receptor for trophic molecules, axonal guidance and cell migration proteins, and neuronal and glial cytoskeletal proteins of various degrees of phosphorylation was examined by immunohistochemistry. Both schizophrenic and control subjects exhibited dystrophic neurites that were immunoreactive for synaptophysin, microtubule-associated proteins (MAP1B), and neurofilament proteins. No major histochemical or morphologic differences in either the expression or distribution of these proteins were observed in the olfactory epithelium of schizophrenic compared to control subjects. These studies indicated that dystrophic neurites frequently occurred in the olfactory mucosa of both schizophrenics and neurologically normal adults. The absence of major immunocytochemical abnormalities suggested that olfactory deficits in schizophrenia may be due to more subtle cellular or molecular differences or to abnormalities in olfactory regions of the central nervous system rather than in the olfactory epithelium.


The Assessment of Depression Inventory (ADI): an appraisal of validity in an outpatient sample.
In this study we examined the validity of the Assessment of Depression Inventory (ADI) using outpatient participants. The ADI Depression scale (Dep) was compared to three other measures used to assess depression: Beck Depression Inventory-II (BDI-II), Zung Self-Rating Depression Scale (ZSDS), and Personality Assessment Inventory (PAI). Correlations between the ADI and these three measures were significant. An analysis of the discriminant ability of the ADI Dep scale resulted in sensitivities, specificities, positive predictive power, negative predictive power, hit rate, and area under the curve (92.3%) that were supportive of the scale's effectiveness. The ADI Feigning scale (Fg) was compared to the six PAI validity scales. The Fg scale correlated significantly with the PAI Negative Impression Management (NIM) and Positive Impression Management (PIM) scales, and the Malingering (MAL) and Defensive (DEF) indexes. Directionality was as would be predicted. The ADI did not correlate with the two PAI validity scales derived by discriminant analysis function.


Exchange coupling of transition-metal ions through hydrogen bonding: a theoretical investigation.
Density functional calculations for full structures of dimers of Cu(II) complexes linked via O-H...O hydrogen bonds provide exchange-coupling constants that are in excellent agreement with experimentally reported values. Magneto-structural correlations between the exchange-coupling constant and the O...O distance or the separation between the coordination planes of the two monomers are analyzed. The calculations support the orbital models usually employed in qualitative interpretations of magneto-structural correlations, showing excellent correlations between the calculated coupling constants and the square of the orbital gap or of the overlap between the two magnetic orbitals. The orbital gap responsible for the antiferromagnetic coupling is seen to result from direct through-space overlap between the oxygen atoms of the two monomers, whereas the hydrogen bonds play an essentially structural role by holding these oxygen atoms in close proximity.


Diffusion kurtosis imaging allows the early detection and longitudinal follow-up of amyloid-β-induced pathology.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly population. In this study, we used the APP/PS1 transgenic mouse model to explore the feasibility of using diffusion kurtosis imaging (DKI) as a tool for the early detection of microstructural changes in the brain due to amyloid-β (Aβ) plaque deposition. We longitudinally acquired DKI data of wild-type (WT) and APP/PS1 mice at 2, 4, 6 and 8 months of age, after which these mice were sacrificed for histological examination. Three additional cohorts of mice were also included at 2, 4 and 6 months of age to allow voxel-based co-registration between diffusion tensor and diffusion kurtosis metrics and immunohistochemistry. Changes were observed in diffusion tensor (DT) and diffusion kurtosis (DK) metrics in many of the 23 regions of interest that were analysed. Mean and axial kurtosis were greatly increased owing to Aβ-induced pathological changes in the motor cortex of APP/PS1 mice at 4, 6 and 8 months of age. Additionally, fractional anisotropy (FA) was decreased in APP/PS1 mice at these respective ages. Linear discriminant analysis of the motor cortex data indicated that combining diffusion tensor and diffusion kurtosis metrics permits improved separation of WT from APP/PS1 mice compared with either diffusion tensor or diffusion kurtosis metrics alone. We observed that mean kurtosis and FA are the critical metrics for a correct genotype classification. Furthermore, using a newly developed platform to co-register the in vivo diffusion-weighted magnetic resonance imaging with multiple 3D histological stacks, we found high correlations between DK metrics and anti-Aβ (clone 4G8) antibody, glial fibrillary acidic protein, ionised calcium-binding adapter molecule 1 and myelin basic protein immunohistochemistry. Finally, we observed reduced FA in the septal nuclei of APP/PS1 mice at all ages investigated. The latter was at least partially also observed by voxel-based statistical parametric mapping, which showed significantly reduced FA in the septal nuclei, as well as in the corpus callosum, of 8-month-old APP/PS1 mice compared with WT mice. Our results indicate that DKI metrics hold tremendous potential for the early detection and longitudinal follow-up of Aβ-induced pathology.


Characterising the extent of misreporting of high blood pressure, high cholesterol, and diabetes using the Australian Health Survey.
Measuring and monitoring the true prevalence of risk factors for chronic conditions is essential for evidence-based policy and health service planning. Understanding the prevalence of risk factors for cardiovascular disease (CVD) in Australia relies heavily on self-report measures from surveys, such as the triennial National Health Survey. However, international evidence suggests that self-reported data may substantially underestimate actual risk factor prevalence. This study sought to characterise the extent of misreporting in a large, nationally-representative health survey that included objective measures of clinical risk factors for CVD. This study employed a cross-sectional analysis of 7269 adults aged 18 years and over who provided fasting blood samples as part of the 2011-12 Australian Health Survey. Self-reported prevalence of high blood pressure, high cholesterol and diabetes was compared to measured prevalence, and univariate and multivariate logistic regression analyses identified socio-demographic characteristics associated with underreporting for each risk factor. Approximately 16 % of the total sample underreported high blood pressure (measured to be at high risk but didn't report a diagnosis), 33 % underreported high cholesterol, and 1.3 % underreported diabetes. Among those measured to be at high risk, 68 % did not report a diagnosis for high blood pressure, nor did 89 % of people with high cholesterol and 29 % of people with high fasting plasma glucose. Younger age was associated with underreporting high blood pressure and high cholesterol, while lower area-level disadvantage and higher income were associated with underreporting diabetes. Underreporting has important implications for CVD risk factor surveillance, policy planning and decisions, and clinical best-practice guidelines. This analysis highlights concerns about the reach of primary prevention efforts in certain groups and implications for patients who may be unaware of their disease risk status.


Improving cardiac regeneration after injury: are we a step closer?
During regeneration, lost functional tissue can, in general, be replaced by different mechanisms, including proliferation of terminally differentiated cells or through differentiation of resident stem cells. It is a well-accepted dogma that the mammalian heart cannot efficiently regenerate upon injury as a consequence of insufficient oxygen supply. This is in sharp contrast to the hearts of adult zebrafish or newts that are able to replace lost ventricular tissue. Novel data indicate that the young murine heart also has the ability to regenerate within the first week after birth using mechanisms apparently quite similar to those observed in fish. This now provides us with a good starting point to identify the molecular mechanisms that led to the loss of the regenerative capacity of the adult mammalian heart. These future studies will also indicate whether it will be possible to reawaken the regenerative capability of cardiomyocytes in the human heart by treatment with selected pharmaceuticals.


trans-Dichloridobis[(6-nicotinoyl-2-pyridyl-κN)(3-pyridyl-κN)methanone]copper(II).
In the title complex, [CuCl(2)(C(17)H(11)N(3)O(2))(2)], the Cu(II) ion is located on an inversion center. It exhibits a distorted octa-hedral coordination geometry defined by two chloride anions at trans sites and four 3-pyridyl N atoms at equatorial sites from two (6-nicotinoyl-2-pyrid-yl)(3-pyrid-yl)methanone ligands. The (6-nicotinoyl-2-pyrid-yl)(3-pyrid-yl)methanone ligand can be viewed as having two pendant 3-pyridyl rings attached to a central pyridyl skeleton via separate carbonyl bridges, acting in a κ(2)N,N'-chelating mode with its 3-pyridyl N atoms bound to the Cu(II) ion. The pendant 3-pyridyl rings make a dihedral angle of 80.76 (5)°. In the crystal, mol-ecules are linked through inter-molecular C-H⋯π and C-H⋯O inter-actions, forming a three-dimentional framework.


Preparation of graphene bilayers on platinum by sequential chemical vapour deposition.
A cheap and flexible method is introduced that enables the epitaxial growth of bilayer graphene on Pt(111) by sequential chemical vapour deposition. Extended regions of two stacked graphene sheets are obtained by, first, the thermal decomposition of ethylene and the subsequent formation of graphene. In the second step, a sufficiently thick Pt film buries the first graphene layer and acts as a platform for the fabrication of the second graphene layer in the third step. A final annealing process then leads to the diffusion of the first graphene sheet to the surface until the bilayer stacking with the second sheet is accomplished. Scanning tunnelling microscopy unravels the successful growth of bilayer graphene and elucidates the origin of moiré patterns.


Jejunal Cavernous Hemangioma Mimicking Malignancy With Increased Activity on 18 F-FDG PET/CT.
A 50-year-old woman underwent 18 F-FDG PET/CT to evaluate possible abdominal malignancy, which was revealed by CT. The images showed a large cystic-solid lesion with peripherally increased FDG activity in the left mid-abdomen. Histopathology of the excised lesion confirmed a jejunal cavernous hemangioma. We reported a rare case of jejunal cavernous hemangioma with FDG accumulation on PET/CT, mimicking malignancy.


The extracellular matrix in IBD: a dynamic mediator of inflammation.
The extracellular matrix (ECM) is a frequently overlooked component of the pathogenesis of inflammatory bowel disease (IBD). However, the functional and clinically significant interactions between immune as well as nonimmune cells with the ECM have important implications for disease pathogenesis. In this review, we discuss how the ECM participates in process associated with IBD that involves diverse cell types of the intestine. Remodeling of the ECM is a consistent feature of IBD, and studies have implicated key ECM molecules in IBD pathogenesis. While the majority of prior studies have focused on ECM degradation by proteases, more recent studies have uncovered additional degrading enzymes, identified fragments of ECM components as potential biomarkers, and revealed that ECM synthesis is increased in IBD. These new studies support the notion that the ECM, rather than acting as a passive element, is an active participant in promoting inflammation. New studies have offered exciting clues about the function of the ECM during IBD pathogenesis. The balance of ECM synthesis and turnover is altered in IBD, and the molecules involved exhibit discreet biological functions that regulate inflammation on the basis of specific cell type and matrix molecule.


PIEZO2 mediates injury-induced tactile pain in mice and humans.
Tissue injury and inflammation markedly alter touch perception, making normally innocuous sensations become intensely painful. Although this sensory distortion, known as tactile allodynia, is one of the most common types of pain, the mechanism by which gentle mechanical stimulation becomes unpleasant remains enigmatic. The stretch-gated ion channel PIEZO2 has been shown to mediate light touch, vibration detection, and proprioception. However, the role of this ion channel in nociception and pain has not been resolved. Here, we examined the importance of Piezo2 in the cellular representation of mechanosensation using in vivo imaging in mice. Piezo2-knockout neurons were completely insensitive to gentle dynamic touch but still responded robustly to noxious pinch. During inflammation and after injury, Piezo2 remained essential for detection of gentle mechanical stimuli. We hypothesized that loss of PIEZO2 might eliminate tactile allodynia in humans. Our results show that individuals with loss-of-function mutations in PIEZO2 completely failed to develop sensitization and painful reactions to touch after skin inflammation. These findings provide insight into the basis for tactile allodynia, identify the PIEZO2 mechanoreceptor as an essential mediator of touch under inflammatory conditions, and suggest that this ion channel might be targeted for treating tactile allodynia.


Diagnostic Impact of Crypt Branching in Patients With Crohn's Disease: A Validation Study.
Crypt branching in inflammatory bowel diseases (IBD) was previously classified into symmetric (CSB) and asymmetric branching (CAB). We aimed to validate the inter-rater agreement of the assessment of crypt branching (also called crypt fission) in patients with Crohn's disease (CD) and to elucidate its potential diagnostic impact. A total of 100 colon biopsies from patients with active CD were analyzed. Two cohorts of patients with ulcerative colitis (UC) and infectious colitis, respectively, served as controls (UC-controls/infectious controls). Three pathologists scored the total number of branching crypts (TBC) as well as the number of CSB and CAB. Inter-rater agreement ranged from moderate to good for TBC and CAB in the study cohort. The study cohort showed significantly higher counts of TBC, CSB, and CAB than the infectious controls (p<0.001 for TBC, p=0.008 for CSB, and p<0.001 for CAB). Cases with CD showed more TBC and CAB compared to cases with UC (p=0.001 each). Inter-rater agreement for crypt branching is reliable in patients with CD. Crypt branching was shown to be an additional histologic feature to distinguish active CD from infectious colitis. Additionally, it could be helpful in the distinction between CD and UC.


SALL4 advances the proliferation and tumor cell stemness of colon cancer cells through the transcription and regulation of ROBO2.
SALL4 is a transcription factor highly expressed in diverse cancers and is implicated in the development of cancer. SALL4 has been implied to play a cancer-promoting role in colon cancer (CC), but the molecular mechanism remains unclear. Chromatin immunoprecipitation assay and dual-luciferase assay were conducted to verify the binding relationship of SALL4 and ROBO2. qRT-PCR detected the mRNA expression levels of SALL4 and ROBO2, and the flow cytometry analyzed the cell cycle distribution. Western blot examined SALL4 expression, and cell cycle/cell stemness-related proteins. The impact of SALL4 and ROBO2 on the proliferation capacity of cells and tumor cell stemness was elucidated by MTT, colony formation, and sphere-forming assays. SALL4 and ROBO2 were up-regulated in CC, and SALL4 could activate the transcription of ROBO2. Down-regulated SALL4 was able to significantly restrain the proliferation capacity of CC cells and arrest the cell cycle in G0/G1 phase by repressing the expression of cyclin B, cyclin E, and cyclin D1. Besides, the rescue assay results indicated that up-regulated ROBO2 could reverse the repressive impact of down-regulated SALL4 on the proliferation of CC cells and accelerate the progression of the cell cycle, thus promoting the sphere-forming of tumor stem cells. SALL4 advanced the proliferation of CC and cell stemness through direct activation of ROBO2 expression, implied the novel mechanism of SALL4 in CC, and pointed out that SALL4/ROBO2 axis was likely to be a potential target for clinical treatment of CC.


Role of 18F-FDG-PET/CT in the management of marginal zone B cell lymphoma.
The use of PET in patients with marginal zone B cell lymphoma (MZL) is controversial because of variability of fluorodeoxyglucose (FDG) avidity. We analyzed 40 PET/CT in 25 consecutive patients to compare its performance with CT at staging and as a first-line response assessment. Sensitivity of PET/CT and CT was 96 and 76%. Mean standard uptake value was 6.1, 6.9 and 3.4 (p = 0.3) in nodal, extranodal and splenic subtypes, respectively. Of 17 patients (extranodal: n = 9; nodal: n = 6; splenic subtype: n = 2) with both imaging tests available at diagnosis, 8 (47%) had more involved areas with PET/CT than with CT, 75% of which were extranodal lesions. PET/CT resulted in upstaging of five patients although treatment of only two of them was changed. Responses of 15 patients with post-treatment PET/CT were the following: 9 negative and 6 positive of which 3 were isolated residual lesions. Progression was documented in two of these three patients. Response was also assessed by CT in 11 patients. Discrepancies were found in three: Two were in complete remission by CT while PET/CT detected localized residual disease; another patient was in partial remission by CT, whereas PET/CT showed only one positive lesion. Two of these three patients relapsed. Patients with negative post-treatment PET/CT did not relapse. With a median follow-up of 50 months (10-152 months), 3-year overall survival was 100 and 80% for patients with negative and positive post-treatment PET/CT (p = 0.2). Three-year disease-free survival was 86%; the negative predictive value (NPV) was 100%, and the positive predictive value (PPV) was 83.3%. Although a larger number of patients will be required to further confirm these data, we can conclude that PET/CT is a useful imaging tool for both staging and response assessment in patients with nodal and extranodal MZL as a result of its high sensitivity, NPV and PPV.


Effects of Vojta approach on diaphragm movement in children with spastic cerebral palsy.
The purpose of this study was to examine the effects of Vojta approach on the gross motor function and diaphragm movement in children with spastic cerebral palsy (CP). Ten children with spastic CP were randomly assigned to a general physiotherapy group (trunk strengthening exercise and gait training) (n=5) and a Vojta approach group (n=5). Interventions were implemented for 30 min per time, 3 times a week for a total of 6 weeks. Ultrasonography was used to measure the areas of the diaphragm (during inspiration, expiration) before and after the interventions, the gross motor function measure (GMFM)-88 was used for evaluation of the gross motor function. In the results of this study, there was a significant difference between before and after GMFM-sitting in the experimental group (P<0.05), a significant difference in changes of inspiration between the two groups (P<0.05). Given these results, Vojta approach may be presented as an effective treatment method for improving sitting position and diaphragm movement during inspiration in children with spastic CP.


Randomized control trial comparing an Alvarado Score-based management algorithm and current best practice in the evaluation of suspected appendicitis.
An objective algorithm for the management of suspected appendicitis guided by the Alvarado Score had previously been proposed. This algorithm was expected to reduce computed tomography (CT) utilization without compromising the negative appendectomy rate. This study attempts to validate the proposed algorithm in a randomized control trial. A randomized control trial comparing the management of suspected acute appendicitis using the proposed algorithm compared to current best practice, with the rate of CT utilization as the primary outcome of interest. Secondary outcomes included the percentage of missed diagnosis, negative appendectomies, length of stay in days, and overall cost of stay in dollars. One hundred sixty patients were randomized. Characteristics such as age, ethnic group, American Society of Anesthesiologist score, white cell count, and symptom duration were similar between the two groups. The overall CT utilization rate of the intervention arm and the usual care arm were similar (93.7% vs 92.5%, p = 0.999). There were no differences in terms of negative appendectomy rate, length of stay, and cost of stay between the intervention arm as compared to the usual care arm (p = 0.926, p = 0.705, and p = 0.886, respectively). Among patients evaluated with CT, 75% (112 out of 149) revealed diagnoses for the presenting symptoms. The proposed AS-based management algorithm did not reduce the CT utilization rate. Outcomes such as missed diagnoses, negative appendectomy rates, length of stay, and cost of stay were also largely similar. CT utilization was prevalent as 93% of the study cohort was evaluated by CT scan. The study has been registered at ClinicalTrials.gov (NCT03324165, Registered October 27 2017).


Basic Transcription Factor 3 Is Required for Proliferation and Epithelial-Mesenchymal Transition via Regulation of FOXM1 and JAK2/STAT3 Signaling in Gastric Cancer.
Gastric cancer (GC) is the most common epithelial malignancy worldwide. Basic transcription factor 3 (BTF3) plays a crucial role in the regulation of various biological processes. We designed experiments to investigate the molecular mechanism underlying the role of BTF3 in GC cell proliferation and metastasis. We confirmed that BTF3 expression was decreased in GC tissues and several GC cell lines. Lentivirus-mediated downregulation of BTF3 reduced cell proliferation, induced S and G2/M cell cycle arrest, and increased apoptosis. Knockdown of BTF3 significantly reduced the expression of Forkhead box M1 (FOXM1). Upregulation of FOXM1 significantly inhibited the decrease in cell proliferation due to BTF3 silencing, S and G2/M cell cycle arrest, and increase in apoptosis. Knockdown of BTF3 decreased Ki-67 and PCNA expression, whereas it increased p27 expression, which was inhibited by upregulation of FOXM1. Knockdown of BTF3 significantly decreased the ability to invade and migrate. Moreover, knockdown of BTF3 increased E-cadherin expression, whereas it decreased N-cadherin and ZEB2 expression, indicating a decrease in epithelial-mesenchymal transition (EMT). Phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) was significantly inhibited by knockdown of BTF3. IL-6-stimulated phosphorylation of STAT3 and JAK2 markedly suppressed inhibition of EMT due to BTF3 silencing. Silencing of BTF3 decreased tumor volume and weight and reduced peritoneal nodules in implanted tumors. Our findings provide a novel understanding of the mechanism of GC and highlight the important role of BTF3/FOXM1 in tumor growth and BTF3/JAK2/STAT3 in EMT and metastasis.


More complicated than it looks: the vagaries of calculating intra-abdominal pressure.
Activities thought to induce high intra-abdominal pressure (IAP), such as lifting weights, are restricted in women with pelvic floor disorders. Standardized procedures to assess IAP during activity are lacking and typically only focus on maximal IAP variably defined. Our intent in this methods article is to establish the best strategies for calculating maximal IAP and to add area under the curve and first moment of the area as potentially useful measures in understanding biologic effects of IAP. Thirteen women completed a range of activities while wearing an intravaginal pressure transducer. We first analyzed various strategies heuristically using data from 3 women. The measure that seemed to best represent maximal IAP was an average of the 3, 5, or 10 highest values, depending on activity, determined using a top-down approach, with peaks at least 1 second apart using algorithms written for Matlab computer software, we then compared this strategy with others commonly reported in the literature quantitatively using data from 10 additional volunteers. Maximal IAP calculated using the top-down approach differed for some, but not all, activities compared with the single highest peak or to averaging all peaks. We also calculated area under the curve, which allows for a time component, and first moment of the area, which maintains the time component while weighing pressure amplitude. We validated methods of assessing IAP using computer-generated sine waves. We offer standardized methods for assessing maximal area under the curve and first moment of the area for IAP to improve future reporting and application of this clinically relevant measure in exercise science.


Developing Machine Learning Algorithms to Predict Pulmonary Complications After Emergency Gastrointestinal Surgery.
Objective: Investigate whether machine learning can predict pulmonary complications (PPCs) after emergency gastrointestinal surgery in patients with acute diffuse peritonitis. Methods: This is a secondary data analysis study. We use five machine learning algorithms (Logistic regression, DecisionTree, GradientBoosting, Xgbc, and gbm) to predict postoperative pulmonary complications. Results: Nine hundred and twenty-six cases were included in this study; 187 cases (20.19%) had PPCs. The five most important variables for the postoperative weight were preoperative albumin, cholesterol on the 3rd day after surgery, albumin on the day of surgery, platelet count on the 1st day after surgery and cholesterol count on the 1st day after surgery for pulmonary complications. In the test group: the logistic regression model shows AUC = 0.808, accuracy = 0.824 and precision = 0.621; Decision tree shows AUC = 0.702, accuracy = 0.795 and precision = 0.486; The GradientBoosting model shows AUC = 0.788, accuracy = 0.827 and precision = 1.000; The Xgbc model shows AUC = 0.784, accuracy = 0.806 and precision = 0.583. The Gbm model shows AUC = 0.814, accuracy = 0.806 and precision = 0.750. Conclusion: Machine learning algorithms can predict patients' PPCs with acute diffuse peritonitis. Moreover, the results of the importance matrix for the Gbdt algorithm model show that albumin, cholesterol, age, and platelets are the main variables that account for the highest pulmonary complication weights.


Efficacy and Safety of Conservative Treatment Compared With Surgical Treatment for Thoracolumbar Fracture With Score 4 Thoracolumbar Injury Classification and Severity (TLICS): A Systematic Review and Meta-analysis.
This was a systematic review and meta-analysis. The clinical outcomes, radiologic outcome, and complications were compared between surgical treatment and conservative treatment of thoracolumbar fractures with a Thoracolumbar Injury Classification and Severity (TLICS) score of 4. The thoracolumbar fracture is the main reason leading to the spinal cord injury. Some studies suggested that the treatment of TLICS=4 is a "gray zone." Hence, the efficacy and safety of surgical treatment and conservative treatment of thoracolumbar fractures with scores 4 TLICS was still debated. A comprehensive search of PubMed, Embase, and the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chongqing VIP Database (VIP), and Wan Fang Database was performed up to October 2021. Relevant studies were identified using specific eligibility criteria and data was extracted and analyzed based on primary and secondary outcomes. A total of 10 studies involving 555 patients were included (3 randomized controlled trials and 7 retrospective studies). There was no significant difference of hospital time (standardized mean difference=0.24, 95% CI: -1.50 to 1.97, P=0.79) and Oswestry Disability Index (mean difference=2.97, 95% CI: -1.07 to 7.01, P=0.15) between surgery and nonsurgery. The length of returning to work was shorter in surgical treatment (standardized mean difference=1.27, 95% CI: 0.07-2.46, P=0.04). Visual Analog Scale in surgical treatment was lower at 1, 3, and 6 months (respectively, P<0.00001, P=0.003, and P=0.02). However, there existed no significant difference between surgical treatment and nonsurgical treatment at 12 and >24 months (respectively, P=0.18 and 0.17). Cobb angle was lower in surgical treatment at postoperative at 6, 12, and >24 months (respectively, P=0.005, P<0.00001, P=0.002, and P=0.0002). Finally, the surgical treatment had a lower incidence of complications (odds ratio=3.89, 95% CI: 1.90-7.94, P=0.0002). Current evidence recommended that surgical treatment is superior to conservative treatment of TLICS score of 4 at the early follow-up. Surgical treatment had lower Cobb angle, Visual Analog Scale scores, and complications compared with a nonsurgical TLICS score of 4. However, these findings needed to be verified further by multicenter, double-blind, and large-sample randomized controlled trials.


Interactions of L-3,5,3'-Triiodothyronine [corrected], Allopregnanolone, and Ivermectin with the GABAA Receptor: Evidence for Overlapping Intersubunit Binding Modes.
Structural mechanisms of modulation of γ-aminobutyric acid (GABA) type A receptors by neurosteroids and hormones remain unclear. The thyroid hormone L-3,5,3'-triiodothyronine (T3) inhibits GABAA receptors at micromolar concentrations and has common features with neurosteroids such as allopregnanolone (ALLOP). Here we use functional experiments on α2β1γ2 GABAA receptors expressed in Xenopus oocytes to detect competitive interactions between T3 and an agonist (ivermectin, IVM) with a crystallographically determined binding site at subunit interfaces in the transmembrane domain of a homologous receptor (glutamate-gated chloride channel, GluCl). T3 and ALLOP also show competitive effects, supporting the presence of both a T3 and ALLOP binding site at one or more subunit interfaces. Molecular dynamics (MD) simulations over 200 ns are used to investigate the dynamics and energetics of T3 in the identified intersubunit sites. In these simulations, T3 molecules occupying all intersubunit sites (with the exception of the α-β interface) display numerous energetically favorable conformations with multiple hydrogen bonding partners, including previously implicated polar/acidic sidechains and a structurally conserved deformation in the M1 backbone.


Identification of prognostic genes in kidney renal clear cell carcinoma by RNA‑seq data analysis.
The present study aimed to analyze RNA-seq data of kidney renal clear cell carcinoma (KIRC) to identify prognostic genes. RNA‑seq data were downloaded from The Cancer Genome Atlas. Feature genes with a coefficient of variation (CV) >0.5 were selected using the genefilter package in R. Gene co‑expression networks were constructed with the WGCNA package. Cox regression analysis was performed using the survive package. Furthermore, a functional enrichment analysis was conducted using Database for Annotation, Visualization and Integrated Discovery tools. A total of 533 KIRC samples were collected, from which 6,758 feature genes with a CV >0.5 were obtained for further analysis. The KIRC samples were divided into two sets: The training set (n=319 samples) and the validation set (n=214 samples). Subsequently, gene co‑expression networks were constructed for the two sets. A total of 12 modules were identified, and the green module was significantly associated with survival time. Genes from the green module were revealed to be implicated in the cell cycle and p53 signaling pathway. In addition, a total of 11 hub genes were revealed, and 10 of them (CCNA2, CDC20, CDCA8, GTSE1, KIF23, KIF2C, KIF4A, MELK, TOP2A and TPX2) were validated as possessing prognostic value, as determined by conducting a survival analysis on another gene expression dataset. In conclusion, a total of 10 prognostic genes were identified in KIRC. These findings may help to advance the understanding of this disease, and may also provide potential biomarkers for therapeutic development.


Synaptic organization of the striatum.
The striatum, the main component of the basal ganglia, is composed of mainly one type of neuron, the so-called medium spiny neuron. This neuron cell type, which constitutes over 90% of striatal neurons, is the major output neuron of the striatum. Combined ultrastructural neuroanatomical methods have elucidated the organization of afferent connectivity to these neurons. The major physiologic function of striatal efferent activity appears to be inhibition of tonically active GABAergic neurons in the globus pallidus and substantia nigra pars reticulata. Thus, the excitatory input from the cerebral cortex, whose afferents make asymmetric synapses with the spines of medium spiny neurons, appears to drive the efferent activity of the striatum. Other extrinsic and intrinsic afferent synapses are situated in a position to regulate the effect of the corticostriatal excitatory input to the medium spiny neurons. For example, dopaminergic afferents from the midbrain make mainly symmetric synapses with the spine necks and dendritic shafts of the medium spiny neurons. Medium spiny neurons themselves have local axon collaterals, in addition to their efferent axon that exits the striatum, which serve to link together local clusters of medium spiny neurons. These local axon collaterals, which contain either GABA, substance P, or enkephalin, also make mainly symmetric synapses with the necks of spines or dendritic shafts of medium spiny neurons. Other afferents with similar synaptic connections to these neurons arise from cholinergic or somatostatinergic striatal intrinsic neurons. Additionally, the patterns of extrinsic and intrinsic afferents to medium spiny neurons and their extrinsic projections are related to the organization of medium spiny neurons into two mosaically organized macroscopic compartments, the striatal patches and matrix.


Cuneate and spinal trigeminal nucleus projections to the cochlear nucleus are differentially associated with vesicular glutamate transporter-2.
There are distinct distributions and associations with vesicular glutamate transporters (VGLUTs) for auditory nerve and specific somatosensory projections in the cochlear nucleus (CN). Auditory nerve fibers project primarily to the magnocellular areas of the ventral cochlear nucleus and deepest layer of the dorsal cochlear nucleus and predominantly colabel with VGLUT1; whereas the spinal trigeminal nucleus (Sp5) projections terminate primarily in the granule cell domains (GCD) of CN and predominantly colabel with VGLUT2. Here, we demonstrate that the terminals of another somatosensory pathway, originating in the cuneate nucleus (Cu), also colabel with VGLUT2. Cu projections in cochlear nucleus exhibited a bilateral distribution pattern with ipsilateral dominance, with 30% of these classified as putative mossy fibers (MFs) and 70% as small boutons (SBs). Cu anterograde endings had a more prominent distribution in the GCD than Sp5, with a higher percentage of MF terminals throughout the CN and higher MF/SB ratio in GCD. 56% of Cu endings and only 25% of Sp5 endings colabeled with VGLUT2. In both cases these were mostly MFs with only 43% of Cu SBs and 18% of Sp5 SBs colabeled with VGLUT2. The few Cu and Sp5 terminals that colabeled with VGLUT1 (11% vs. 1%), were evenly distributed between MFs and SBs. The high number of VGLUT2-positive Cu MFs predominantly located in the GCD, may reflect a faster-acting pathway that activates primarily dorsal cochlear nucleus cells via granule cell axons. In contrast, the higher percentage of Sp5-labeled SB terminals and a greater number of projections outside the GCD suggest a slower-acting pathway that activates both dorsal and ventral cochlear nucleus principal cells. Both projections, with their associations to VGLUT2 likely play a role in the enhancement of VGLUT2 after unilateral deafness [Zeng C, Nannapaneni N, Zhou J, Hughes LF, Shore S (2009) J Neurosci 29:4210-4217] that may be associated with tinnitus.


Risks of blood transfusion and their prevention.
As a result of significant progress in reducing the risks of transfusion-transmitted viral infections, bacterial contamination of platelet components (1:2,000) and sepsis (1:50,000) are now the most frequent infectious complications of blood transfusions. Sepsis from bacterial contamination of red cell components is less frequent (1:500,000), because red blood cells, unlike platelet components, can be stored at refrigerated temperatures (1 degrees C-4 degrees C). Current risks for transfusion-transmitted viral diseases (per blood component transfused) are: human immunodeficiency virus, 1:2,135,000; hepatitis C virus, 1:1,935,000; hepatitis B virus, 1:205,000; and human T-lymphotropic viruses, 1:2,993,000. Transfusion-transmitted babesiosis has increased morbidity and mortality for splenectomized patients. Immunocompromised recipients are at increased risk of developing Chagas disease from blood contaminated by Trypanosoma cruzi. Reports of transfusion-related acute lunge injury and transfusion-associated graft-versus-host disease increase each year as physicians become increasingly aware of their varied clinical presentations. While strategies for preventing infections complications focus primarily on blood donor services, individual physicians can reduce risks to their patients by maintaining conservative "triggers" for transfusions, prescribing pharmacologic agents to reduce bleeding (antifibrinolytic drugs, serine protease inhibitors, fibrin sealants), and using epoetin alpha to reduce transfusion of red cells in selected patients.


[Fatal electric accident due to adverse error situation].
Despite wearing high-impedance shoes, a young male died while trying to connect a garden pump (230 V). The cause of death could easily be determined on the basis of testimonies of eye-witnesses and an electric mark on the body. Histological and electron microscopic examinations showed metallisation of the electric mark (pure iron). Intensive investigative efforts were needed, however, to reproduce the current path, which resulted from three different coactive failures. The electrotechnical characteristics of the case and the resulting current path are described.


SMN Blood Levels in a Porcine Model of Spinal Muscular Atrophy.
Spinal Muscular Atrophy (SMA) is an autosomal recessive motor neuron disease that results in loss of spinal motor neurons, muscular weakness and, in severe cases, respiratory failure and death. SMA is caused by a deletion or mutation of the SMN1 gene and retention of the SMN2 gene that leads to low SMN expression levels.The measurement of SMN mRNA levels in peripheral blood samples has been used in SMA clinical studies as a pharmacodynamic biomarker for response to therapies designed to increase SMN levels. We recently developed a postnatal porcine model of SMA by the viral delivery of a short-hairpin RNA (shRNA) targeting porcine SMN (pSMN). scAAV9-mediated knockdown of pSMN mRNA at postnatal day 5 results in denervation, weakness and motor neuron and ventral root axon loss that begins 3-4 weeks after viral delivery, and this phenotype can be ameliorated by subsequent viral delivery of human SMN (hSMN). To determine if the effect of modulating SMN levels using gene therapy can be measured in blood. We measured expression of pSMN mRNA and hSMN mRNA by quantitative droplet digital PCR (ddPCR). We found that the endogenous expression of pSMN mRNA in blood increases in the first month of life. However, there were no significant differences in blood levels of pSMN mRNA after knock-down or of human SMN mRNA after gene therapy. Our results, obtained in a large animal model of SMA that is similar in size and anatomy to human infants, suggest that measurement of SMN mRNA levels in blood may not be informative in SMA clinical trials involving intrathecal delivery of SMN-modulating therapies.


An intersectional approach to understanding LGBTQ+ people of color's access to LGBTQ+ community resilience.
Resiliency research suggests that connection to LGBTQ + communities helps mitigate the negative impacts of oppression (i.e., community resilience). However, due to various interlocking systems of oppression, those with multiple marginalized identities [i.e., LGBTQ + people of color (POC)] may not have equal access to LGBTQ + community resilience resources. Despite the growing body of literature, little research has explored LGBTQ + POC's experiences with the LGBTQ + community from an intersectional framework to critique systems of oppression and provide implications for social justice. Fourteen LGBTQ + POC participated in semistructured interviews to explore their experiences with protective factors of the LGBTQ + community and the barriers they face in accessing community resilience. Findings supported three broad categories with subthemes: (1) LGBTQ + Community Resilience Resources (i.e., Shared Narratives and Feeling Seen and Social Justice and Liberation), (2) Inequity to Accessing LGBTQ + Community Resilience (i.e., Alienation and Exclusion, Disempowerment and Exploitation, and Invisibility), and (3) Making Space. Utilizing our intersectional framework, we provide implications for social justice advocacy as well as clinical and educational implications for counseling psychologists and community organizations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Carcass composition and mammary development responses to photoperiod and plane of nutrition in Holstein heifers.
Twenty prepubertal heifers (averaging 155 kg body weight) were assigned to one of four treatment groups in an experiment of 2 X 2 factorial design. The main effects were photoperiods of 8 h light:16 h dark (8L:16D) vs 16L:8D, and LOW vs HIGH plane of nutrition. Heifers on the LOW plane of nutrition were fed to achieve a growth rate of approximately .7 kg/d; daily feed intake was restricted with no orts and was identical in both groups of heifers subjected to either 8 or 16 h of light daily. Heifers on the HIGH plane of nutrition were fed ad libitum to achieve a growth rate greater than 1 kg/d. All heifers were slaughtered during the luteal phase of an estrous cycle at an average body weight of 337, 334, 360 and 349 kg for 8L:16D-LOW plane, 16L:8D-LOW plane, 8L:16D-HIGH plane and 16L:8D-HIGH plane groups, respectively. Average time on treatment was 233, 236, 206 and 181 d and average estimated carcass weight gain was .39, .40, .55 and .61 kg/d, respectively. Within LOW or HIGH planes of nutrition, photoperiod did not affect live body weight gains. A photoperiod of 16L:8D, compared with 8L:16D, increased protein content in the 9-10-11th rib section of heifers on HIGH nutrition (16.2 vs 14.6%), but not in heifers fed the LOW plane of nutrition (15.5 vs 16.1%). However, within 8L:16D groups, HIGH plane reduced rib section protein content as compared with LOW plane of nutrition (14.6 vs 16.1%); there was no difference observed within 16L:8D groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Preventing running injuries. Practical approach for family doctors.
To present a practical approach for preventing running injuries. Much of the research on running injuries is in the form of expert opinion and comparison trials. Recent systematic reviews have summarized research in orthotics, stretching before running, and interventions to prevent soft tissue injuries. The most common factors implicated in running injuries are errors in training methods, inappropriate training surfaces and running shoes, malalignment of the leg, and muscle weakness and inflexibility. Runners can reduce risk of injury by using established training programs that gradually increase distance or time of running and provide appropriate rest. Orthoses and heel lifts can correct malalignments of the leg. Running shoes appropriate for runners' foot types should be selected. Lower-extremity strength and flexibility programs should be added to training. Select appropriate surfaces for training and introduce changes gradually. Prevention addresses factors proven to cause running injuries. Unfortunately, injury is often the first sign of fault in running programs, so patients should be taught to recognize early symptoms of injury.


Elevated LHRH levels in human milk.
Anterior pituitary gonadotropins are regulated by the hypothalamic peptide hormone LHRH. However, the extrahypothalamic source(s) as well as extrapituitary action(s) of LHRH exist. We describe the discovery of relatively elevated levels of LHRH in human milk and its possible functions in the neonates. Blood and milk samples were obtained at the same time in post-partum period from lactating mothers. Special methods of extraction and concentration of milk as well as plasma LHRH were developed, and the hormone levels were determined by a sensitive double antibody radioimmunoassay using 125I-LHRH of high specific activity and immunoreactivity. Human milk contained 5 to 6 times more LHRH than plasma samples. The pure milk LHRH was fully biologically active when tested in vivo. Another hypothalamic hormone, TRH, is not found in such high concentrations in milk, only 5% that of LHRH. This excludes the possibility of an in vivo concentrating mechanism for the hypothalamic LHRH. Since LHRH neurons possess only minute amounts of the hormone, which is released in hypophyseal portal circulation, the large amounts present in the milk of lactating mothers may be of extrahypothalamic origin. Partial absorption of intact LHRH from intestine is known. The elevated levels of milk LHRH may have a profound influence in certain biological processes in the neonatal life, in continuation of the intrauterine exposure to high levels of LHRH of placental origin.


Development of tolerance to alpha-2 adrenergic agonists in the vascular system of the rat after chronic treatment with clonidine.
The possibility of development of tolerance after chronic treatment with clonidine (CLN) was investigated in the vascular system of the rat. Rats were treated with CLN for 3 to 10 days by dissolving the drug in the drinking water at concentrations of 0.1 to 10 micrograms/ml. Pressor responses to several vasoconstrictors were examined after pithing. Rats given CLN-containing water at a concentration of 10 micrograms/ml were considered as receiving CLN at about 1 mg/kg/day and were found to be subsensitive to l-norepinephrine. Decrease in the sensitivity varied with the length of CLN treatment and the maximum decrease was attained within 5 days of the treatment. Recovery from the subsensitivity required a long deprivation time of CLN; after 10 days of treatment, 14 days of deprivation did not cause any recovery in the sensitivity. The subsensitivity also was observed in the alpha-2 adrenergic agonists, CLN and azepexole, whereas it was not detected in alpha-1 adrenergic agents, phenylephrine and methoxamine, and the nonadrenergic vasoconstrictors, angiotensin-II and Lys-vasopressin. Pressor responses to stimulation of the complete sympathetic outflow also decreased in the CLN-treated rats. These results show clearly that chronic treatment with CLN makes rat vasculature subsensitive to l-norepinephrine and suggest that this phenomenon involves specific desensitization developed in the contractile mechanisms of vascular smooth muscles mediated by alpha-2 adrenergic receptors.


Sites of termination of in vitro DNA synthesis on ultraviolet- and N-acetylaminofluorene-treated phi X174 templates by prokaryotic and eukaryotic DNA polymerases.
In vitro DNA synthesis on a phi X174 template primed with a restriction fragment and catalyzed by the Escherichia coli DNA polymerase I large (Klenow) fragment (pol I) terminates at the nucleotide preceding a site that has been altered by ultraviolet irradiation or treatment with N-acetylaminofluorene. Termination on ultraviolet-irradiated templates is similar when synthesis is catalyzed by E. coli DNA polymerase III holoenzyme (pol III), phage T4 DNA polymerase, a polymerase alpha from human lymphoma cells, or avian myeloblastosis virus reverse transcriptase. 3' leads to 5' exonuclease activity cannot be detected in the reverse transcriptase and DNA polymerase alpha preparations. On N-acetylaminofluorene templates, pol I, pol III, and T4 polymerase reactions terminate immediately preceding the lesion, whereas reverse transcriptase-catalyzed reactions and, at some positions in the sequence, polymerase alpha-catalyzed reactions terminate at the site of the lesion. Substitution of Mn2+ for Mg2+ changes the pattern of pol I-catalyzed termination sites. The data suggest that termination is a complicated process that does not depend exclusively on the 3' leads to 5' exonuclease activity associated with many polymerases.


Office management of urinary stomas.
The postoperative care of stoma patients is truly life long. With the excellent stoma equipment available, no patient should be a "stoma cripple." New advances in continent reservoirs will improve patient acceptance and lessen the fear associated with stomas. Finally, close follow-up by both the enterostomal therapy nurse and the surgeon is essential for the complete care of the stoma patient.


A philosophical taxonomy of ethically significant moral distress.
Moral distress is one of the core topics of clinical ethics. Although there is a large and growing empirical literature on the psychological aspects of moral distress, scholars, and empirical investigators of moral distress have recently called for greater conceptual clarity. To meet this recognized need, we provide a philosophical taxonomy of the categories of what we call ethically significant moral distress: the judgment that one is not able, to differing degrees, to act on one's moral knowledge about what one ought to do. We begin by unpacking the philosophical components of Andrew Jameton's original formulation from his landmark 1984 work and identify two key respects in which that formulation remains unclear: the origins of moral knowledge and impediments to acting on that moral knowledge. We then selectively review subsequent literature that shows that there is more than one concept of moral distress and that explores the origin of the values implicated in moral distress and impediments to acting on those values. This review sets the stage for identifying the elements of a philosophical taxonomy of ethically significant moral distress. The taxonomy uses these elements to create six categories of ethically significant moral distress: challenges to, threats to, and violations of professional integrity; and challenges to, threats to, and violations of individual integrity. We close with suggestions about how the proposed philosophical taxonomy of ethically significant moral distress sheds light on the concepts of moral residue and crescendo effect of moral distress and how the proposed taxonomy might usefully guide prevention of and future qualitative and quantitative empirical research on ethically significant moral distress.


Mineralized Collagen Regulates Macrophage Polarization During Bone Regeneration.
The host immune response to bone biomaterials is vital in determining the fate of scaffolds and also the outcomes of bone regeneration. Mineralized collagen is an ideal tissue-engineering scaffold for bone repair; however, little is known about its immunomodulatory properties after implantation. In this study, extrafibrillarly-mineralized collagen (EMC) and intrafibrillarly-mineralized collagen (IMC) scaffolds with different nanostructures were fabricated and their immunomodulatory properties via macrophage polarization during bone regeneration were investigated. Micro-CT findings showed that the IMC scaffold yielded more new bone formation than the EMC scaffold. In the defect area, more CD68 + CD163 + M2-like macrophages were observed in the IMC group, while M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) increased dramatically in the EMC group. We further demonstrated, from the protein and RNA levels, that M2-associated anti-inflammatory cytokines interleukin (IL)-10 and arginase-1 were highly expressed in the macrophages seeded on the IMC scaffold, while those seeded on the EMC scaffold expressed more M1-related genes iNOS and IL-6. Moreover, the macrophage polarization in response to the nanostructure of mineralized collagen scaffolds influenced the osteogenesis of human bone marrow stromal cells. These findings suggest that the nanostructure of mineralized collagen scaffolds affects macrophage functional polarization during bone regeneration. The immunomodulatory properties of biomaterial scaffolds can be a dictator of bone regeneration outcomes.


The lacrimal gland expresses nuclear retinoid X receptors.
The lacrimal gland expresses nuclear retinoic acid receptors. This suggests that retinoids are involved in control of gene expression in the lacrimal gland. Retinoid X receptors (RXRs) form heterodimers with and are required for activation of retinoic acid receptors. The purpose of this study was to identify retinoid X receptors in the lacrimal gland. Total RNA was purified from rat, rabbit and human lacrimal glands and from cultured rat lacrimal cells. RNA was analyzed by northern blotting using cDNA probes for RXR alpha, RXR beta and RXR gamma. Nuclear protein extracts from rat and rabbit lacrimal glands were probed for RXR beta by immunoblotting, using a mouse monoclonal antibody. RXR alpha mRNA transcripts (5 kb) and RXR beta mRNA transcripts (3.3 kb) are present in the lacrimal glands of all species studied and in cultured rat lacrimal cells. RXR gamma mRNA (1.9 kb) was detected only in the rabbit lacrimal gland. RXR beta is expressed as a 50 kDa protein in rat and rabbit lacrimal glands. This study confirms the presence of RXRs in the lacrimal gland, thereby supporting a role for retinoids and their nuclear receptors in the control of gene transcription in the lacrimal gland.


Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro.
Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug-drug interactions.


Antiviral agents.
Only a few agents with antiviral activity are available for regular clinical use. Amantadine hydrochloride is effective in the prophylaxis of influenza A2. Idoxuridine and adenine arabinoside have found application as topical agents in the treatment of herpes simplex keratitis. Adenine arabinoside is also under investigation in the treatment of disseminated infections due to herpes zoster and herpes simplex. Ribavirin, an agent with a wide spectrum of activity in vitro, has not fulfilled expectations in clinical trials. Because of the near eradication of smallpox, methisazone has become less important as a prophylactic agent in smallpox.