BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.
Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.


Optimizing Mass Spectrometry Analyses: A Tailored Review on the Utility of Design of Experiments.
Mass spectrometry (MS) has emerged as a tool that can analyze nearly all classes of molecules, with its scope rapidly expanding in the areas of post-translational modifications, MS instrumentation, and many others. Yet integration of novel analyte preparatory and purification methods with existing or novel mass spectrometers can introduce new challenges for MS sensitivity. The mechanisms that govern detection by MS are particularly complex and interdependent, including ionization efficiency, ion suppression, and transmission. Performance of both off-line and MS methods can be optimized separately or, when appropriate, simultaneously through statistical designs, broadly referred to as "design of experiments" (DOE). The following review provides a tutorial-like guide into the selection of DOE for MS experiments, the practices for modeling and optimization of response variables, and the available software tools that support DOE implementation in any laboratory. This review comes 3 years after the latest DOE review (Hibbert DB, 2012), which provided a comprehensive overview on the types of designs available and their statistical construction. Since that time, new classes of DOE, such as the definitive screening design, have emerged and new calls have been made for mass spectrometrists to adopt the practice. Rather than exhaustively cover all possible designs, we have highlighted the three most practical DOE classes available to mass spectrometrists. This review further differentiates itself by providing expert recommendations for experimental setup and defining DOE entirely in the context of three case-studies that highlight the utility of different designs to achieve different goals. A step-by-step tutorial is also provided.


Non-Renal Lesions of Uraemia in Domestic Cats.
Uraemia is a clinical syndrome caused by an increase in uraemia-associated toxins in the bloodstream as a consequence of intrinsic kidney or lower urinary tract diseases. Cats seem to be more affected by urinary tract diseases than dogs, particularly considering that chronic kidney disease (CKD) is one of the most important conditions in cats. Considering the lack of information on the systemic lesions of uraemia in cats, the aim of this study was to investigate the prevalence and clinical and pathological aspects of non-renal lesions in uraemic cats, with special attention to the differences between cats and dogs. Cats necropsied between 2000 and 2019 (n = 1,330) were investigated for urinary tract diseases and non-renal lesions of uraemia. The prevalence of uraemic cats with non-renal lesions (n = 78) was 5.8%. Adult, elderly and male animals were predominantly affected. Anorexia, apathy and vomiting were the most common clinical signs and CKD was observed in the majority of uraemic cats. Pulmonary oedema was the most frequent non-renal lesion identified. In contrast with previous reports, haemorrhagic and ulcerative gastritis was frequently observed, whereas soft tissue mineralization and parathyroid hyperplasia were uncommon features. Fibrous osteodystrophy was not observed. Cats with urinary tract diseases did not have as wide a variety of non-renal uraemic lesions as uraemic dogs and multisystemic manifestation of uraemia was observed in only 24.4% of cases.


Profiling tissue-resident T cell repertoires by RNA sequencing.
Deep sequencing of recombined T cell receptor (TCR) genes and transcripts has provided a view of T cell repertoire diversity at an unprecedented resolution. Beyond profiling peripheral blood, analysis of tissue-resident T cells provides further insight into immune-related diseases. We describe the extraction of TCR sequence information directly from RNA-sequencing data from 6738 tumor and 604 control tissues, with a typical yield of 1 TCR per 10 million reads. This method circumvents the need for PCR amplification of the TCR template and provides TCR information in the context of global gene expression, allowing integrated analysis of extensive RNA-sequencing data resources.


Properties of a novel D-stereospecific aminopeptidase from Ochrobactrum anthropi.
A novel aminopeptidase active toward D-amino acid-containing peptides, D-amino acid amides, and D-amino acid esters has been purified 2,800-fold to homogeneity from a bacterium Ochrobactrum anthropi SCRC C1-38, which had been isolated from soil. The enzyme has a molecular weight of about 122,000 and is composed of two identical subunits (Mr = 59,000). The optimal pH for activity was 8.0. It showed strict D-stereospecificity toward substrates including low molecular weight D-amino acid amides such as D-alanine amide, D-alpha-aminobutyric acid amides, and D-serine amide; D-alanine N-alkylamides such as D-alanine-p-nitroanilide, D-alanine benzylamide, and D-alanine n-butylamide; and peptides with a D-alanine at the NH2 terminus such as D-alanylglycine, D-alanylglycylglycine, D-alanyl-L-alanyl-L-alanine, and D-alanine oligomers. Generally, the enzyme did not act on substrates composed of L-amino acid at the NH2 terminus, although it showed low stereospecificity only toward substrates such as the methyl esters of L-alanine, L-serine, and L-alanine-p-nitroanilide. Comparing the Km and Vmax values for the major substrates, it is clear that the enzyme prefers peptides to amino acid arylamides or amino acid amides. The enzyme was tentatively named as "D-aminopeptidase." EDTA and divalent cations have no effect on the enzyme activity. The enzyme appears to be a thiol peptidase.


[Seasonal variations in the manifestation of psychiatric diseases].
The admission data of the psychiatric unit of the Hannover Medical School for the period 1973 to 1981 were studied by time-series analysis (Box and Jenkins 1970). The total number of admissions as well as subgroups formed according to diagnosis, sex and age did not show any seasonal variations.


The prosocial benefits of seeing purpose in life events: A case of cultural selection in action?
Norenzayan et al. propose that religious beliefs with incidental prosocial effects propagated via a long-term process of cultural evolution. Applying their model, I explore a possible candidate target of cultural selection: the teleological view - often culturally elaborated as a belief in karma or fate - that life events occur to punish or reward individuals' moral behavior.


Central nervous system pathology in preclinical MPS IIIB dogs reveals progressive changes in clinically relevant brain regions.
Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24-30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.


Comparison of dipyridamole stress echocardiography and perfusion scintigraphy for cardiac risk stratification in vascular surgery patients.
Dipyridamole single-photon emission computed tomography (SPECT) has a high negative predictive value for perioperative cardiac events, but events are infrequent in patients with a positive test. In contrast, dipyridamole echocardiography is more selective for detection of multivessel disease and thus may have a greater specificity for cardiac events. We therefore compared the ability of dipyridamole SPECT and echocardiography to predict perioperative and long-term cardiac events in 133 patients referred for vascular surgery. The group was also evaluated based on clinical features and ejection fraction. Four patients had surgery cancelled because of high risk and were excluded from further analysis. Among the 129 remaining patients, 21 had coronary revascularization (n=12) or an early cardiac end point (n=9). The sensitivity of SPECT for the prediction of early events (90%) was not significantly different from that of echocardiography (66%, p=NS). The specificity of SPECT (68%) was less than that of echocardiography (88%, p <0.001%), as was the accuracy (72% vs 84%, p=0.02). These findings were replicated after exclusion of patients with treatment end points. During long-term follow-up, 12 patients experienced > or = 1 event: 6 died from cardiac causes, 4 underwent revascularization, and 3 had myocardial infarction. Thus, the specificity of SPECT and echocardiography for late events were 58% and 80%, respectively (p <0.001). The 3-year survival of patients without ischemia during echocardiography or at SPECT was not different (93% vs 94%, p=NS).


[Embryonal carcinoma of the ovary. Anatomo-clinical aspects and presentation of a case].
A case of ovarian embryonic carcinoma in a 25 year old patient hospitalized in the Gynecological Department of the National Cancer Institute, Naples, is described. After a general introduction the clinical condition of the patient is discussed with emphasis on the histological aspects of the neoplasm.


Further insights into release mechanisms from nano-emulsions, assessed by a simple fluorescence-based method.
Nano-emulsion consists of a dispersion of oil droplets sizing below 200 nm, in aqueous continuous phase, and generally stabilized by low-molecular-weight surfactants. These stable nano-carriers are able to encapsulate and transport lipophilic molecules poorly soluble in water. However, the question on the leakage and release mechanisms of an active pharmaceutical ingredient, from oil nano-droplets to an acceptor medium has not been clearly addressed. Herein, we developed a simple fluorescence approach based on self-quenching of lipophilic fluorophore-based on Nile Red (NR668) to monitor cargo transfer from lipid nano-droplets to the acceptor medium. In this method, the fluorophore release can be monitored by the increase in its fluorescence quantum yield and the blue shift in its emission spectrum. The studies of the release process allow emphasizing an important role of the bulk aqueous medium in controlling the droplet to droplet fluorophore transfer and the attained equilibrium. The developed methodology could be applied to monitor release of other lipophilic dyes and it could help to better understand the cargo release from nanocarriers.


The developmental morphology of Torpedo marmorata: electric organ--myogenic phase.
The early development of the electric organ of Torpedo marmorata has been examined by light and electron microscopy to the 40-mm stage of embryo growth. The myogenic nature of this tissue is confirmed ultrastructurally by the presence of myoblasts and myotubes both containing myofibrils cross striated with Z,A and I bands. Fusion between these cells is also found taking place. A scheme is presented to explain the development of the overall structural plan of the organ and specifically the formation of the future electrocyte columns. AT 40 mm, a series of morphological transformations signals the onset of a divergent developmental pattern ultimately leading to the establishment of mature electrocyte columns. These features include rounding up of myotubes, dissolution of myofibrils and the appearance of intermediate size filaments (11 nm) and perhaps a non-muscular actin (5.5 nm). This early myogenic phase of development occurs in the absence of any specific nervous contact even though electromotor nerves are always in close proximity.


Liposomes containing monophosphoryl lipid A: a potent adjuvant system for inducing antibodies to heroin hapten analogs.
In order to create an effective immunization approach for a potential vaccine to heroin, liposomes containing monophosphoryl lipid A [L(MPLA)] were tested as an adjuvant system to induce antibodies to heroin hapten analogs. Four synthetic haptens and two immunization strategies were employed. In the first strategy, a hydrophobic 23 amino acid immunogenic peptide derived from the membrane proximal external region of gp41 from HIV-1 envelope protein was embedded as a carrier in the outer surface of L(MPLA), to which was conjugated a 15 amino acid universal T cell epitope and a terminal heroin hapten analog. In the second strategy, tetanus toxoid (TT) carrier protein was decorated with haptens by conjugation, and the hapten-conjugated protein was mixed with L(MPLA). After immunization of mice, each of the immunization strategies was effective for induction of IgG anti-hapten antibodies. The first immunization strategy induced a mean end-point IgG titer against one of two haptens tested of approximately 12,800; however, no detectable antibodies were induced against the liposome-associated HIV-1 carrier peptide. In the second immunization strategy, depending on the hapten used for decorating the TT, end-point IgG titers ranged from 100,000 to 6,500,000. In this strategy, in which hapten was conjugated to the TT, end-point IgG titers of 400,000 to the TT carrier were observed with each conjugate. However, upon mixing unconjugated TT with L(MPLA), anti-TT titers of 6,500,000 were observed. We conclude that L(MPLA) serves as a potent adjuvant for inducing antibodies to candidate heroin haptens. However, antibodies to the carrier peptide or protein were partly or completed inhibited by the presence of conjugated hapten.


Complement activation mediated by mannan-binding lectin in plasma from healthy individuals and from patients with SLE, Crohn's disease and colorectal cancer. Suppressed activation by SLE plasma.
We have developed a method for quantitating mannan-binding lectin (MBL)-induced activation of the complement system (MBL-C4-AC) in human plasma. This method and an assay for MBL concentration were applied to plasma samples from healthy individuals and patients with systemic lupus erythematosus (SLE), Crohn's disease (CD) and colorectal cancer (CRC). The MBL concentration was measured by an enzyme-linked immunosorbent assay (ELISA) using monoclonal anti-MBL-antibodies and MBL-C4-AC by an ELISA using solid-phase mannan, incubating with plasma samples and quantitating the complement (C) activation by the use of antibodies against the C split-products C4b/C4c. The MBL concentration was nonsignificantly elevated in plasma from SLE-patients, whereas MBL-C4-AC was suppressed (P < 0.04). There was no correlation between MBL concentration and MBL-C4-AC in plasma from SLE-patients. In contrast, a significant correlation was found between the MBL concentration and MBL-C4-AC in plasma from healthy individuals. The C4 concentration was significantly reduced (P < 0.002) in plasma from the SLE patients and showed a significant correlation to MBL-C4-AC. The MBL-C4-AC assay was highly effective in discriminating the SLE patients from the other patient groups and healthy individuals.


Analysis of hyaluronan content in chondroitin sulfate preparations by using selective enzymatic digestion and electrospray ionization mass spectrometry.
Two important glycosaminoglycans (GAGs) with structural roles in the body's cartilage are hyaluronan (HA) and chondroitin sulfate (CS). A simple mass spectrometric method for determining the amount of HA that may be present in isolated CS samples is presented in this article. Samples are subjected to selective enzymatic digestion using a bacterial hyaluronidase (HA lyase, EC 4.2.2, from Streptococcus dysgalactiae) specific for HA. Undigested CS GAG is then removed by centrifugal filtration, and digested HA left in the filtrate is quantified by electrospray ionization mass spectrometry using an internal standard and selected ion monitoring. The described method was applied to the analysis of several CS samples prepared for use in nutritional supplements.


The effect of ketanserin on blood pressure and platelets during cardiopulmonary bypass.
Ketanserin, a serotonin antagonist, was used to control blood pressure during cardiopulmonary bypass in 12 patients having cardiac surgery. The drug was administered as a 10 mg bolus followed by a continuous infusion of either 40, 80, or 120 mg/hr to maintain mean arterial blood pressure below 70 mm Hg. There were 16 hypertensive episodes of which 15 (93.7%) were successfully controlled with ketanserin. Mean arterial pressure decreased significantly from an average of 72 +/- 3 to 52 +/- 9 mm Hg after 1 min. The effect that ketanserin had on platelets was also evaluated. Neither adverse nor salutary effects were seen in the platelet count, though a significant inhibition of serotonin-induced platelet aggregation was observed. Ketanserin proved effective for controlling hypertension during cardiopulmonary bypass but, despite inhibition of serotonin-induced platelet aggregation, it did not prevent thrombocytopenia.


Cyclo-oxygenase isoenzymes. Structural basis for selective inhibition of cyclo-oxygenases by anti-inflammatory agents.
Cyclo-oxygenase (prostaglandin endoperoxide synthase) is the enzyme which metabolizes the conversion of arachidonic acid to prostaglandin. It exists in at least two isoforms: the constitutive (cyclo-oxygenase-1) and the inducible (cyclo-oxygenase-2) which is controlled by a number of factors, including cytokines and intracellular messengers. These enzymes are the therapeutic targets of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen. The cyclo-oxygenase active site is a long, hydrophobic, channel where the substrate arachidonic acid gains access to the active site. Cyclo-oxygenase-2 differs form cyclo-oxygenase-1 in certain key characteristics, particularly important is the valine/leucine substitution at position 523 that creates a defect in the inner shell of the cyclo-oxygenase-2 enzyme channel leaving a side pocket by which drugs selective for cyclo-oxygenase-2 gain access. Although cyclo-oxygenase-1 seems to be expressed in physiological conditions and cyclo-oxygenase-2 in inflammatory conditions, it is not yet possible to identify all their different roles. Cyclo-oxygenase-2 may be expressed constitutively, whereas the generation of prostaglandin by cyclo-oxygenase-2 may replace that by cyclo-oxygenase-1 in some situations (or vice-versa). Both cyclo-oxygenase isoenzymes contribute to mucosal defence and the inhibition of the two isoforms contributes to the pathogenesis of non-steroidal anti-inflammatory drug-induced gastric damage.


Allelochemicals of Pinus halepensis as drivers of biodiversity in Mediterranean open mosaic habitats during the colonization stage of secondary succession.
The Mediterranean region is recognized as a global biodiversity hotspot. However, over the last 50 years or so, the cessation of traditional farming has given way to strong afforestation at the expense of open habitats. Pinus halepensis Miller, known to synthesize a wide range of secondary metabolites, is a pioneer expansionist species colonizing abandoned agricultural land that present high species richness. Here, laboratory bioassays were used to study the potential impact of P. halepensis on plant diversity through allelopathy, and the role of microorganisms in these interactions. Germination and growth of 12 target species naturally present in fallow farmlands were tested according to concentration of aqueous extracts obtained from shoots of young pines (aged about 5 years), with or without the presence of soil microorganisms (autoclaved or natural soil). Under the highest concentrations and autoclaved soil, more than 80 % of target species were germination and/or growth-inhibited, and only two species were non-sensitive. Under more natural conditions (lower extracts concentrations and natural soil with microorganisms), only 50 % of species were still inhibited, one was non-sensitive, and five were stimulated. Thus, microorganisms alter the expression of allelochemicals released into the ecosystem, which highlights their key role in chemical plant-plant interactions. The results of allelopathic experiments conducted in the lab are consistent with the community patterns observed in the field. These findings suggest that allelopathy is likely to shape vegetation composition and participate to the control of biodiversity in Mediterranean open mosaic habitats.


Greater fat oxidation with diacylglycerol oil consumption for 14 days compared with triacylglycerol oil consumption in overweight men and women.
Several studies have reported increased fat oxidation with diacylglycerol (DAG) oil consumption. However, the effects of long-term DAG oil consumption on energy metabolism remain to be investigated. The objective of this study was to compare the effects of 14 days of either DAG or triacylglycerol (TAG) oil consumption on substrate oxidation, energy expenditure (EE) and dietary fat oxidation. Eight males and six females participated in this randomized, double-blind, crossover feeding study. Each patient consumed the 14-day controlled test diet containing either 10 g day(-1) of DAG or TAG oil for acclimatization before a respiratory chamber measurement, followed by a 2-week washout period between diet treatments. Substrate oxidation and EE were measured in the respiratory chamber at the end of each dietary treatment. The patients consumed test oil as 15% of total caloric intake in the respiratory chamber (mean test oil intake was 36.1+/-6.6 g day(-1)). Twenty-four hour fat oxidation was significantly greater with 14 days of DAG oil consumption compared with TAG oil consumption (78.6+/-19.6 and 72.6+/-14.9 g day(-1), respectively, P<0.05). There were no differences in body weight or body composition between diet treatments. Dietary fat oxidation was determined using the recovery rate of (13)CO(2) in breath, and was significantly enhanced with DAG oil consumption compared with TAG oil consumption, measured over 22 h after ingestion of (13)C-labelled triolein. Resting metabolic rate (RMR) was significantly greater with DAG oil consumption compared with TAG oil consumption (1766+/-337 and 1680+/-316 kcal day(-1), respectively, P<0.05). Consumption of DAG oil for 14 days stimulates both fat oxidation and RMR compared with TAG oil consumption, which may explain the greater loss of body weight and body fat with DAG oil consumption that has been observed in weight-loss studies.


Nitric oxide-induced programmed cell death in human neuroblastoma cells is accompanied by the synthesis of Egr-1, a zinc finger transcription factor.
Nitric oxide (NO) is cytotoxic for human SH-SY5Y neuroblastoma cells. While nuclear condensation was visible in cells treated with nitric oxide donors, we observed that the plasma membrane remained intact, indicating that NO induced apoptotic cell death. We analyzed the NO-induced apoptotic signaling cascade in SH-SY5Y cells and observed a striking increase in early growth response (Egr)-1 promoter activity as a result of NO-induced cell death. Likewise, we detected an activation of the transcriptional activation potential of the ternary complex factor Elk1, a key transcriptional regulator of serum response element-driven gene transcription. Egr-1 is a zinc finger transcription factor that couples extracellular signals to long-term responses by altering expression of Egr-1 target genes. The Egr-1 5'-flanking region contains five serum response elements (SRE) that function as genetic elements for stimulus-transcription coupling. Moreover, these SREs are binding sites for Elk1, suggesting that NO activated Egr-1 gene transcription via activation of Elk1. The NO-induced biosynthesis of Egr-1 was confirmed by Western blot analysis and an NO-dependent increase in the transcriptional activation potential of Egr-1 was observed. The fact that NO-induced neuronal cell death is accompanied by the biosynthesis of Egr-1 suggests that Egr-1 may be an integral part of the NO triggered apoptotic signaling cascade.


The use of caesium sulphate density gradient centrifugation to analyse proteoglycans from human articular cartilages of different ages.
Proteoglycan subunits from human articular cartilage were fractionated by caesium sulphate density gradient centrifugation. A single heterogeneous population of molecules was produced whose average density decreased with increasing age of the individual from which they were obtained. At no density did the carbohydrate composition of any adult fraction resemble that of any newborn fraction, although there was considerable overlap in density. However, there was a similarity in amino acid composition between the most dense proteoglycans from the adult and those of least density from the newborn. The carbohydrate content of a 2-year-old proteoglycan was intermediate in composition, with high density fractions resembling the newborn and low density fractions resembling the adult. In addition, the proteoglycans of lowest density in both the newborn and two year preparations showed additional bands on agarose/polyacrylamide gel electrophoresis resembling the adult material. These results indicate that while a core protein of adult composition may occur in the juvenile proteoglycan it need not necessarily be glycosylated in an adult manner, suggesting that glycosylation is to some extent independent of the origin of core protein heterogeneity.


Simultaneous extraction, separation, isolation and identification of endogenous components from Etlingera elatior by pressurized matrix solid-phase dispersion using liquid chromatography-mass spectrometry.
From the analytical chemistry point-of-view, an ideal sample preparation method should be simple, rapid, automatic, selective, precise, exhaustive, reproducible and protect the analyte-of-interest from degradation. In this study, a novel sample preparation method, named pressurized matrix solid-phase dispersion (p-MSPD) extraction was developed for simultaneously extracting, separating, purifying, isolating, and analyzing endogenous components in a solid sample matrix. Etlingera elatior, a traditional medicinal plant known as the torch ginger, was applied as a sample matrix to evaluate the p-MSPD process. The entire extraction, separation, isolation, fractionation and detection were performed automatically with a commercial LC-MS system. The novel method was satisfactorily applied for the preparation of real samples without optimization, which had the ability to selectively isolate pure compounds from the solid sample matrix for further NMR analysis. Therefore, the method is recommended for quality control of traditional medicines, research efforts when sample amounts are limited, and laboratories that have ordinary LC-MS instrumentation.


Association of serum gamma-glutamyltransferase with chronic kidney disease risk: a meta-analysis.
Studies on the association between gamma-glutamyltransferase (GGT) and chronic kidney disease (CKD) have produced conflicting results. This study aimed to investigate the association of elevated GGT with the risk of CKD in the adult general population by performing a meta-analysis of relevant articles. We searched PubMed, Web of Science, and Embase databases from their inception to October 2017 to identify observational studies regarding the association between serum GGT level and CKD. Pooled risk ratio (RR) and 95% confidence intervals (CI) was calculated as the effective measures. Eight studies with 116 011 individuals were included in this meta-analysis. Overall, individuals with the highest versus the lowest GGT level were not associated with an increased risk of CKD (RR 1.14; 95% CI 0.99-1.31). Subgroup analysis showed that the pooled RR for the highest versus the lowest GGT category was 1.31 (95% CI 1.06-1.60) for the Asian countries and 1.04 (95% CI 0.88-1.23) for the Western countries. In the sex-stratified analysis, no significant associations of elevated GGT with risk of CKD were found for both women (RR 0.95; 95% CI 0.84-1.07) and men (RR 1.08; 95% CI 0.86-1.36). This meta-analysis demonstrates no significant association between elevated serum GGT and risk of CKD in the adult general population. However, future well-designed studies are needed to evaluate the impact of geographical region on the association.


Postoperative changes after bilateral mandibular osteotomies: a computed tomography study.
Twelve patients undergoing bilateral osteotomy of the ramus of the mandible were examined with CT preoperatively and postoperatively. The maximum area of the cheek and oropharynx was measured together with the thickness of the masseter muscle and the overlying subcutaneous tissue. The preoperative CT examinations showed wide anatomic variations. The postoperative examinations showed a diminished oropharynx lumen of approximately 43%. Swelling of the cheek averaged 61% and was associated with the well-vascularized masseter muscle. The TMJs were measured and a slight widening of the joint space was found postoperatively.


Poikilodermatous mycosis fungoides with CD30-positive large cell transformation successfully treated by brentuximab vedotin.
We present a patient with a 33-year history of poikilodermatous mycosis fungoides (MF) who subsequently developed CD30-positive large cell transformation. After 6 years of conventional MF treatment, side effects of therapy and/or concomitant diseases prevented the previously applied treatment modalities. The CD30-directed antibody-cytotoxic drug conjugate (brentuximab vedotin) was introduced and followed by quick and excellent therapeutic response.


Three-dimensional J-resolved H-1 magnetic resonance spectroscopic imaging of volunteers and patients with brain tumors at 3T.
A method that combines two-dimensional (2D) J-resolved spectroscopy with three spatial dimension magnetic resonance spectroscopic imaging (MRSI) is introduced to measure J-coupled metabolites of glutamate (Glu), glutamine (Gln), myo-Inositol (mI), and lactate (Lac) in the brain and to simultaneously obtain T(2) values of choline (Cho), creatine (Cr), and N-acetyl aspartate (NAA). Relatively few points in the t(1) dimension (six echo times) and a flyback echo-planar trajectory were incorporated in the acquisition to speed up the total acquisition time so that it was within a clinically feasible range (23 min). Data obtained using GAMMA software simulations and from phantoms have shown that the (4)CH(2) resonances of Glu can be separated from Gln at 2.35 ppm in TE-averaged spectra. Results from phantoms, six normal volunteers, and four patients demonstrated good signal-to-noise ratio (SNR). The J cross-peaks from the methyl group of Lac were visualized in the 2D spectra from the phantom and the glioma patient, and could be quantified from the spectra at J = +/-4.17 Hz. This technique also enables the evaluation of the changes in metabolite T(2). Compared with the values in normal white matter, the T(2) values of Cho and Cr were statistically significantly increased in regions of glioma.


Signal Information Prediction of Mortality Identifies Unique Patient Subsets after Severe Traumatic Brain Injury: A Decision-Tree Analysis Approach.
Nonlinear physiological signal features that reveal information content and causal flow have recently been shown to be predictors of mortality after severe traumatic brain injury (TBI). The extent to which these features interact together, and with traditional measures to describe patients in a clinically meaningful way remains unclear. In this study, we incorporated basic demographics (age and initial Glasgow Coma Scale [GCS]) with linear and non-linear signal information based features (approximate entropy [ApEn], and multivariate conditional Granger causality [GC]) to evaluate their relative contributions to mortality using cardio-cerebral monitoring data from 171 severe TBI patients admitted to a single neurocritical care center over a 10 year period. Beyond linear modelling, we employed a decision tree analysis approach to define a predictive hierarchy of features. We found ApEn (p = 0.009) and GC (p = 0.004) based features to be independent predictors of mortality at a time when mean intracranial pressure (ICP) was not. Our combined model with both signal information-based features performed the strongest (area under curve = 0.86 vs. 0.77 for linear features only). Although low "intracranial" complexity (ApEn-ICP) outranked both age and GCS as crucial drivers of mortality (fivefold increase in mortality where ApEn-ICP <1.56, 36.2% vs. 7.8%), decision tree analysis revealed clear subsets of patient populations using all three predictors. Patients with lower ApEn-ICP who were >60 years of age died, whereas those with higher ApEn-ICP and GCS ≥5 all survived. Yet, even with low initial intracranial complexity, as long as patients maintained robust GC and "extracranial" complexity (ApEn of mean arterial pressure), they all survived. Incorporating traditional linear and novel, non-linear signal information features, particularly in a framework such as decision trees, may provide better insight into "health" status. However, caution is required when interpreting these results in a clinical setting prior to external validation.


Intra-arterial thrombolytic therapy for acute anterior spinal artery stroke.
Spinal cord infarction is rare but can be extremely disabling. Prompt diagnosis and treatment of these infarcts is important for patient outcomes. While intravenous thrombolytic therapy is a well-established form of treatment in circumstances of cerebral stroke, it has only recently been successfully used in a few incidents of spinal cord ischemia. We present a case of anterior spinal artery (ASA) territory ischemia treated with ASA intra-arterial thrombolytic therapy. A 52-year-old male presented with acute onset of severe lumbar pain, rapidly progressing paraplegia and loss of pain and temperature sensation, with preservation of proprioception and vibratory sensation at the L1 level and below on the right and at the L3 level and below on the left. MRI showed restricted diffusion involving the cord at and below L1 level, with normal cord T2 signal. Digital subtraction spinal angiography showed ASA cutoff in the descending limb at the level of L1. Intra-arterial tissue plasminogen activator (t-PA) combined with verapamil and eptifibatide was administered within the ASA and the patient had significant neurological improvement immediately postoperatively and at 8-month clinical follow-up. Direct ASA intra-arterial thrombolysis is feasible, and this drug combination might be an effective therapy for spinal stroke.


Maternal weight loss associated with hyperemesis gravidarum: a predictor of fetal outcome.
Over a 5-year period in our center 64 patients were hospitalized with a diagnosis of hyperemesis gravidarum. Patients were classified into two groups to determine whether weight loss was an objective predictor of pregnancy outcome. Patients whose weight loss was greater than 5% of their prepregnancy weight were classified as group A (n = 30). Patients with nausea and vomiting of pregnancy but with maintenance of at least 95% of prepregnancy body weight were in group B (n = 34). Infants in group A were significantly smaller with respect to average birth weight expressed as a percentile for gestational age: 38.11 percentile, versus 72.00 percentile for group B (p less than 0.025). Macrosomia (greater than or equal to 4000 gm) was significantly associated with group B (18% versus group A, 0%; p less than 0.025). Growth retardation (less than or equal to 10th percentile weight at birth) was significantly associated with group A (30% versus group B, 6%; p less than 0.01). Three integumentary system abnormalities (3 of 30 cases) occurred in group A compared with none in group B. Although hyperemesis gravidarum has been viewed as a positive predictor, those patients who also demonstrate weight loss and electrolyte disturbance may be a distinct entity and at greater risk for growth retardation and fetal anomalies.


Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility.
Changes to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.


Anaphylactoid reactions to neuromuscular blocking agents: a commonly undiagnosed condition?
A group of 28 patients with extreme, life-threatening sensitivity to suxamethonium was identified and 15 were studied in detail by skin-testing. The female/male ratio was 8/1. Sensitivity may be present without previous exposure to suxamethonium; in 3 patients reactions occurred during the first exposure to anaesthesia. Most patients showed one or more cross-sensitivities to alcuronium, tubocurarine, and gallamine. Signs of circulatory collapse were the sole presenting feature in 50% of the patients. Histamine release induced by the drug in vitro was demonstrated in some instances.


Use of perceived effort ratings to control exercise intensity in young healthy adults.
The purpose of this study was to evaluate the use of the rating of perceived exertion (RPE) as a means of regulating the intensity of exercise during running. The subjects were healthy, relatively fit young adults (16 men and 12 women). Estimates of effort were recorded using the Borg 6-20 Scale whilst the maximal oxygen uptake of the subjects was measured as they ran on an electrically driven treadmill. In a further session, the same subjects were requested to run on the treadmill at constant exercise intensity based on their interpretation of levels 9, 13 and 17 of the Borg Scale. They regulated their running speed and the treadmill gradient but had no knowledge of performance from the equipment display panel. A linear regression analysis was carried out to examine the relationship between heart rate, perceived exertion and relative metabolic demand. This revealed that the rating of perceived exertion was at least as good a predictor of exercise intensity as heart rate in both the graded exercise test and effort production test. The results support the view that RPE may be used to predict relative metabolic demand, especially at higher workloads and could be a useful medium for controlling intensity of effort during vigorous exercise in such subjects.


Differential effects of methylmercury on the synthesis of protein species in dorsal root ganglia of the rat.
Dorsal root ganglia from control and methylmercury (MeHg)-treated rats were incubated in vitro with 35S-methionine ant the proteins synthesized were analyzed by two-dimensional electrophoresis. The double labelling method, in which proteins of control dorsal root ganglia labelled in vitro with 3H-leucine were added to each of the two samples as an internal standard, was used to minimize unavoidable errors arising from the resolving procedure itself. The results obtained showed that the effect of MeHg on the synthesis of proteins in dorsal root ganglia was not uniform for individual protein species in the latent period of MeHg intoxication. Among 200 protein species investigated, 157 showed inhibition of synthesis close to that of the total proteins in the tissue (68% of the control). Among the remaining protein species, 20 showed real stimulation of synthesis, whereas 7 were moderately inhibited and 16 were inhibited more strongly than the total proteins in the tissue. These results suggest that the effect of MeHg on the synthetic rates for protein species in dorsal root ganglia differs with the species, and that unusual elevation or reduction of the synthesis of some protein species caused by MeHg may lead to impairment of normal nerve functions.


Menkes' Kinky hair syndrome: studies of copper metabolism and long term copper therapy.
A patient with Menkes' kinky hair syndrome was treated with oral CuSO4. Plasma copper, ceruloplasmin, red cell copper, and 24-hr urine copper excretion remained essentially unchanged. Intravenous copper infusion resulted in a rise of serum ceruloplasmin. During administration of a test meal of 64Cu(NO3)2, the patient was given alternately a volume of 0.9% NaCl or an equal volume of plasma intravenously. Radioactivity found in the blood was unchanged after each infusion period. During 427 days of subcutaneous copper, plasma p-phenylenediamine oxidase activity and plasma copper rose toward normal. Subsequent balance studies showed that the patient was in negative copper balance because of large losses in feces. Scanning electron microscopy demonstrated persistent pili torti.


Open gaps in the evolution of the eukaryotic nucleotide excision repair.
Nucleotide excision repair (NER) is the most versatile DNA repair pathway as it removes different kinds of bulky lesions. Due to its essential role for genome integrity, it has appeared early in the evolution of species. However, most published studies are focused on humans, mice, yeast or bacteria. Considering the large amount of information on genome databases, it is currently possible to retrieve sequences from NER components in many organisms. Therefore, we have characterized the potential orthologs of 10 critical components of the human NER pathway in 12 eukaryotic species by using similarity and structural criteria through the use of bioinformatics tools. This approach has allowed us to characterize gene and protein structures comparatively, taking a glance at some evolutionary aspects of the NER pathway. We have obtained significant search results for the majority of the proteins in most of the organisms studied, mainly for factors that play a pivotal role in the pathway. However, we have revisited significant differences and found new aspects that may imply a distinct functioning of this pathway in different organisms. Through the demonstration of the heterogeneity of the gene structures and a variety in the protein architecture of the NER components evaluated, our results show important differences between human NER and evolutionarily distant eukaryotes. We highlight the lack of a canonical XPD in chicken, the divergence of XPA in plants and protozoans and the absence of XPE in the invertebrate species analyzed. In spite of this, it is remarkable the presence of this excision repair mechanism in a high number of evolutionary distant organisms, being present since the origin of eukaryotes.


Molecular analysis of Kaposi's sarcoma occurring during haemodialysis.
Human Herpesvirus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). In this paper we attempted to confirm the connection between dialysis, HHV-8, and KS by examining the case of an elderly haemodialysis nonimmunosuppressed male patient with end-stage renal disease, who developed KS. By using PCR we have verified the presence of DNA from two different genomic regions (ORF 26 and ORF K1) of HHV-8. In addition, our RT-PCR results suggest active replication of HHV-8 in blood and KS lesions of the patient. Phylogenetic analysis revealed identical DNA sequence to ORF K1, and a close relation to its C1 variant. In conclusion, we document the case of KS and HHV-8 coexistence in a Greek elderly patient undergoing regular haemodialysis. Furthermore, our results indicate that factors other than immunosuppression could lead to KS development possibly due to activation of HHV-8.


Effects of Icaritin on the physiological activities of esophageal cancer stem cells.
Icaritin is a compound extracted from herb, recent study have found it is able to influence the activity of various types of cancer. Our aim was to investigate the effects of Icaritin on the physiological activities of esophageal cancer stem cells (CSCs). In this study, esophageal cancer cells were cultured and CD133 positive esophageal CSCs were sorted by flow cytometry. Changes in the physiological activity of esophageal CSCs following treatment with different concentrations of Icaritin (0, 12.5, 25, 50, and 100 μmol/L) were evaluated. The CCK-8 method and Transwell assay were used to determine the effects of Icaritin on the proliferation, migration, and invasion of esophageal CSCs. Flow cytometery was used to investigate its effect on the apoptosis of CSCs. The effect of Icaritin on the expression of proteins in Wnt and Hedgehog signaling pathways were determined using western blot test. Consequently, Icaritin inhibited the proliferation, migration, and invasion of esophageal CSCs in a dose-dependent manner. It promoted cell apoptosis, and influenced the levels of proteins in Wnt and Hedgehog signaling pathways. It may act as a promising drug in the therapy of esophageal cancer.


A case report of a septic hip secondary to a psoas abscess.
Psoas abscess was first described by Mynter in 1881. Though rare, its prevalence is increasing with advances in radiology and an increasing ability to accurately diagnose the condition. The symptoms of a psoas abscess can be insidious and nonspecific, and patients often present with a limp, fever, weight loss, and flank or abdominal pain.A psoas abscess can be classified as either primary or secondary depending on the presence or absence of an underlying disease. Primary psoas abscess has become more prevalent in the developed world, especially in immuno-compromised patients.We present the case of a 48 year old man who presented with fever, left hip pain and difficulty weight-bearing. He had a past medical history of chronic renal failure secondary to hypertension. Following laboratory, radiological and microbiological analyses the patient was diagnosed as having a Staphylococcus Aureus hip sepsis secondary to a psoas abscess.Psoas abscess should be included as a differential diagnosis in all patients presenting with hip pain and constitutional symptoms. The case is discussed with reference to the literature.


Virtual magnetic resonance elastography predicts the intraoperative consistency of meningiomas.
Virtual magnetic resonance elastography (vMRE) is an experimental imaging modality designed to non-invasively predict the haptic properties of tissues. The modality is sensitive to tissue stiffness and fibrosis. Information about meningioma consistency prior to resection is of great interest in neurological surgery as the surgical plan and outcome may be affected by the tumor's stiffness. In this study, we assessed the ability of vMRE to predict the intraoperative consistency and mechanical heterogeneity of intracranial meningiomas. We included 12 patients scheduled for meningioma resection, of which one patient was found to have a solitary fibrous tumor on histological examination. All participants underwent preoperative vMRE and intraoperative consistency grading. Intraoperative qualitative consistency correlated positively with vMRE-based consistency assessment (odds ratio 5.63, 95% CI 1.12-28.30, p = 0.04) at b1000. Mechanically homogenous tumors had significantly lower ∆ mean stiffness than heterogeneous tumors (8.13 vs 18.07 kPa, p = 0.01). This study thus demonstrates a possible clinical application of vMRE in predicting the intraoperative consistency and mechanical heterogeneity of meningiomas.


Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers.
To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.


Possible association of a new translocation, t(7;11)(p15;p15), with Ph1 chromosome-negative chronic myelogenous leukemia.
A Ph1 chromosome-negative chronic myelogenous leukemia (CML) with t(7;11)(p15;p15) in a 6-year-old girl is reported. Three cases of 7;11 translocation have been reported so far. The patients concerned were between 37 and 72 years of age; 2 of them had CML and the other had acute myelomonocytic leukemia. Data from these 4 cases suggest that the 7;11 chromosome translocation may be related to a subgroup of Ph1-negative CML, specifically to one that may easily proceed to blast phase, or to "subacute" myelogenous leukemia. The present case demonstrates that CML with this chromosome abnormality is not restricted to adults but also affects children. The t(1;11)(q21 or 23;p15) reported in another case with Ph1-negative CML may be a variant of this translocation.


Detection and isolation of immune complexes in multiple sclerosis cerebrospinal fluid.
Immune complexes were studied in the cerebrospinal fluid (CSF) of 20 multiple sclerosis (MS) and 20 other neurological disease (OND) patients using polyethylene glycol precipitation; ten samples from each group were also examined using gel chromatography followed by ELISA. Polyethylene glycol detected predominantly IgG and IgM complexes in 13 of 20 MS samples and four of 20 OND samples. Intact MS complexes ranged in size from 230 to 340 kDa and contained 64 and 53 kDa antigens. Gel chromatography detected IgA complexes in eight of ten MS samples and one of ten OND samples; these complexes appeared to consist of polymeric IgA rather than true antigen. Chromatography detected IgG complexes in nine of ten MS and four of ten OND samples. Intact MS complexes ranged from 240 to 320 kDa and contained 200 and 150 kDa antigens. This study suggests that immune complexes are a very frequent finding in the CSF of MS patients and are in sufficient quantity to visualize on gel electrophoresis.


Bilateral Vaginocutaneous Fistulas Three Years following the Insertion of a "Tension-Free" Vaginal Tape.
We present a rare complication of fistula following the insertion of a transvaginal tape and the literature surrounding fistula formation following this procedure.


The emergent role of artificial intelligence, natural learning processing, and large language models in higher education and research.
Artificial Intelligence (AI) has revolutionized various domains, including education and research. Natural language processing (NLP) techniques and large language models (LLMs) such as GPT-4 and BARD have significantly advanced our comprehension and application of AI in these fields. This paper provides an in-depth introduction to AI, NLP, and LLMs, discussing their potential impact on education and research. By exploring the advantages, challenges, and innovative applications of these technologies, this review gives educators, researchers, students, and readers a comprehensive view of how AI could shape educational and research practices in the future, ultimately leading to improved outcomes. Key applications discussed in the field of research include text generation, data analysis and interpretation, literature review, formatting and editing, and peer review. AI applications in academics and education include educational support and constructive feedback, assessment, grading, tailored curricula, personalized career guidance, and mental health support. Addressing the challenges associated with these technologies, such as ethical concerns and algorithmic biases, is essential for maximizing their potential to improve education and research outcomes. Ultimately, the paper aims to contribute to the ongoing discussion about the role of AI in education and research and highlight its potential to lead to better outcomes for students, educators, and researchers.


Explorations of New SHG Materials in Mercury Iodate Sulfate System.
Through systematic experiments, two novel mercury iodate sulfates, namely, Hg2 (IO3 )2 (SO4 )(H2 O) and Hg2 (IO3 )2 (SO4 ) were obtained. They crystallize in monoclinic space group C2 and C2/c, respectively. Hg2 (IO3 )2 (SO4 )(H2 O) exhibits the [Hg(IO3 )]+ polar cationic layer inherited from Hg(IO3 )2 and the three-dimensional (3D) framework inherited from HgSO4 . This enables Hg2 (IO3 )2 (SO4 )(H2 O) to generate a strong second harmonic generation (SHG) response of 6 times that of KH2 PO4 (KDP). The structure of Hg2 (IO3 )2 (SO4 ) is very similar to that of Hg2 (IO3 )2 (SO4 )(H2 O), and they can be transformed into each other. Hg2 (IO3 )2 (SO4 )(H2 O) shows a large optical band gap of 3.98 eV and a high dehydration temperature of 250 °C. This study indicates that by reasonable design, the introduction of multiple functional groups into a compound may combine their advantages to achieve good overall optical performance.


Macroautophagic phenomena in renin granules.
The secretory granules of murine epithelioid cells take up and probably degrade mitochondria; they thus appear to have macroautophagic properties. As renin granules also have other properties uncommon for secretory granules, they are suggested to fulfill functions in these cells otherwise reserved for lysosomes.


Effectiveness of prescribing codes in reducing inappropriate proton pump inhibitors in ambulatory care.
Health care deciders are aware of the inappropriate use of proton pump inhibitors (PPIs). To reduce inappropriate prescriptions, the Conseil du Médicament (CdM) issued a practice guideline and the Régie de l'Assurance Maladie du Quebec (RAMQ) asked prescribers to justify its use by writing a specific indication code for their patients to obtain drug coverage. This study aimed to evaluate the effectiveness of the intervention by the RAMQ to reduce inappropriate PPI prescription. A cross-sectional quasi-experimental prospective study was performed in an emergency department. Patients aged 18 years or older were included in 2016 to 2017 and 2019 to 2021 in the pre- and postintervention group, respectively. The proportion of patients on PPI without an appropriate indication were identified from patient interviews and chart review. A total of 871 and 1475 patients were recruited in the pre- and postintervention groups. According to the CdM guideline, the proportion of inappropriate PPI prescription was 30.7% (n = 267) in the preintervention group and 49.1% (n = 724) in the postintervention group (P < 0.001). According to the RAMQ criteria, the proportion of inappropriate PPI prescription was of 76.1% (n = 663) and 81.4% (n = 1200) in the pre- and postintervention group, respectively (P < 0.001). This study highlights the ineffectiveness of the codes for PPI prescriptions in reducing inappropriate prescriptions. It seems that the obligation to write a code does not lead to a reassessment of PPI indication.


Novel Quantitative PCR for Rhodococcus equi and Macrolide Resistance Detection in Equine Respiratory Samples.
R. equi is an important veterinary pathogen that takes the lives of many foals every year. With the emergence and spread of MDR R. equi to current antimicrobial treatment, new tools that can provide a fast and accurate diagnosis of the disease and antimicrobial resistance profile are needed. Here, we have developed and analytically validated a multiplex qPCR for the simultaneous detection of R. equi and related macrolide resistance genes in equine respiratory samples. The three sets of oligos designed in this study to identify R. equi housekeeping gene choE and macrolide resistance genes erm(46) and erm(51) showed high analytic sensitivity with a limit of detection (LOD) individually and in combination below 12 complete genome copies per PCR reaction, and an amplification efficiency between 90% and 147%. Additionally, our multiplex qPCR shows high specificity in in-silico analysis. Furthermore, it did not present any cross-reaction with normal flora from the equine respiratory tract, nor commonly encountered respiratory pathogens in horses or other genetically close organisms. Our new quantitative PCR is a trustable tool that will improve the speed of R. equi infection diagnosis, as well as helping in treatment selection.


Comparative development of heavily asymmetric-cordate gametophytes of Anemia phyllitidis (Anemiaceae) focusing on meristem behavior.
Development of heavily asymmetric cordate gametophytes of Anemia phyllitidis (Anemiaceae), one of the schizaeoid ferns, was examined using a sequential observation technique; epi-illuminated light micrographs of the same growing gametophytes were taken approximately every 24 h. The apical cell-like wedge-shaped cell was produced once from the terminal cell of a germ filament, but it stopped dividing soon after production of one or two derivative cells. Without a functional apical cell, the gametophyte developed by intercalary growth until the early stage of wing formation, and then the multicellular (pluricellular) meristem arose from the lower lateral side of the gametophyte. This was in sharp contrast to the observation that the multicellular meristem forms in place of the apical cell in typical cordate gametophytes. Loss of the functional apical cell probably caused a site-shift in the multicellular meristem of the Anemia phyllitidis gametophyte during evolution from apical to lateral. The results suggest that apical cell-based and multicellular meristems are primarily independent of each other. The multicellular meristem produced cells equally in the distal and proximal directions to form wings in both directions but proximally produced cells divided much less frequently. As a result, a heavily asymmetric gametophyte was formed.


Data security in information systems by language analysis.
The paper describes how a language analyser (parser) is used as interface between a user and the functions of an information system. A specific user is at log-on forced into a sublanguage analyser, which only recognizes statements relevant to this specific user. Every attempt to use non-allowed functions is rejected, and the user is guided into his sublanguage. The language analyser is defined completely separately from the semantics of the information system, and it can be automatically generated outgoing from a definition of language functions.


Relationships between watershed emergy flow and coastal New England salt marsh structure, function, and condition.
This study evaluated the link between watershed activities and salt marsh structure, function, and condition using spatial emergy flow density (areal empower density) in the watershed and field data from 10 tidal salt marshes in Narragansett Bay, RI, USA. The field-collected data were obtained during several years of vegetation, invertebrate, soil, and water quality sampling. The use of emergy as an accounting mechanism allowed disparate factors (e.g., the amount of building construction and the consumption of electricity) to be combined into a single landscape index while retaining a uniform quantitative definition of the intensity of landscape development. It expanded upon typical land use percentage studies by weighting each category for the intensity of development. At the RI salt marsh sites, an impact index (watershed emergy flow normalized for marsh area) showed significant correlations with mudflat infauna species richness, mussel density, plant species richness, the extent and density of dominant plant species, and denitrification potential within the high salt marsh. Over the 4-year period examined, a loading index (watershed emergy flow normalized for watershed area) showed significant correlations with nitrite and nitrate concentrations, as well as with the nitrogen to phosphorus ratios in stream discharge into the marshes. Both the emergy impact and loading indices were significantly correlated with a salt marsh condition index derived from intensive field-based assessments. Comparison of the emergy indices to calculated nitrogen loading estimates for each watershed also produced significant positive correlations. These results suggest that watershed emergy flow is a robust index of human disturbance and a potential tool for rapid assessment of coastal wetland condition.


Hypoxia regulates CD9 expression and dissemination of B lymphoblasts.
Acute lymphoblastic leukemias (ALL) are the most frequent cancer in children and derive most often from B-cell precursors. Current survival rates roughly reach 90% at 10 years from diagnosis. However, 15-20% of children still relapse with a significant risk of death. Our previous work showed that the transmembrane protein CD9 plays a major role in lymphoblasts migration into sanctuary sites, especially in testis, through the activation of RAC1 signaling upon blasts stimulation with C-X-C chemokine ligand 12 (CXCL12). Here, we identified common factors shared by the bone marrow and extramedullary niches which could upregulate CD9 expression and function. We found that low oxygen levels enhance CD9 expression both at mRNA and protein levels. We further determined that Hypoxia Inducible Factor 1α (HIF1α), the master transcription factor involved in hypoxia response, binds directly CD9 promoter and induce CD9 transcription. We also showed that CD9 protein is crucial for leukemic cell adhesion and migration at low oxygen levels, possibly through its action on RAC1 signaling. Mouse xenograft experiments indicate that HIF1α signaling pathway promotes ALL cells engraftment in a CD9-dependent manner. The present work increments our understanding of CD9 implication in ALL pathogenesis.


A brief cancer pain assessment tool in Japanese: the utility of the Japanese Brief Pain Inventory--BPI-J.
Despite recognition that pain management is an important component in the treatment of Japanese cancer patients, progress in this area has been slowed by the lack of an appropriate measure of pain. In a prospective, single-institution study, a Japanese translation of the Brief Pain Inventory (BPI-J) was administered to 121 patients to assess the intensity and impact of cancer-related pain. After an analysis of the instrument's reliability and validity, this study tested the utility of the new measure in an analysis of the adequacy of analgesic prescription. Results were compared with predictive models from studies using non-Japanese patient groups. Factor analysis of the BPI items resulted in two factors, pain severity and pain interference, showing consistency with other language versions of the tool. Coefficient alphas of greater than 0.80 for the items comprising these two subscales indicate a reliable self-report pain instrument. After establishing the validity and reliability of the BPI-J, we examined possible predictors of inadequate pain management in these Japanese cancer patients. Similar to studies done in other countries, women patients and those whose pain severity was underestimated by their physician were more likely to be undermanaged for pain. The results of this study support the utility of the Japanese BPI for studies of the epidemiology of cancer pain in Japan, as well as for the assessment of pain treatment outcome in Japanese-speaking patients.


Associations of nonrestorative sleep and insomnia symptoms with incident depressive symptoms over 1-2 years: Longitudinal results from the Hispanic Community Health Study/Study of Latinos and Sueño Ancillary Study.
Nonrestorative sleep (NRS), defined as insufficiently rested or refreshed sleep, is considered to play an important role in the development of depression. The aim of this study is to investigate the predictive ability of insomnia-related symptoms, including NRS, for incident depressive symptoms (DEPs) in a longitudinal manner. We used data of 1196 samples aged 18-64 years who participated in both the Hispanic Community Health Study/Study of Latinos conducted in 2008-2010 and the follow-up study (Sueño Ancillary Study) conducted in 2010-2013. DEPs and insomnia-related symptoms (difficulty initiating sleep [DIS], difficulty maintaining sleep [DMS], early morning awakening [EMA], difficulty returning to sleep [DRS], and NRS) were evaluated by the 10-item Center for Epidemiologic Studies Depression Scale and the Women's Health Initiative Insomnia Rating Scale, respectively. A logistic regression analysis was used to evaluate the predictive ability of each insomnia-related symptom at baseline for incident DEPs in couple-years. In the univariate logistic regression analysis, all insomnia-related symptoms had significant associations with incident DEPs (DIS, odds ratio [OR] = 1.6; DMS, OR = 1.6; EMA, OR = 1.5; DRS, OR = 1.9; NRS, OR = 2.5). After adjusting for sociodemographic factors and the confounding effects of other insomnia-related symptoms, only NRS (OR = 2.2, 95% confidence interval = 1.4-3.5, p = .001) was significantly associated with incident DEPs. NRS was a risk factor for incident DEPs, which includes a predictive ability for other insomnia-related symptoms. Our results suggest that focusing on NRS is an effective strategy for preventing depression in public health promotions.


On the reintroduction of the Mhorr gazelle in Tunisia and Morocco.
The Mhorr gazelle (Gazella dama mhorr) became extinct in the wild in the 1960s. The current world zoo population amounts to some 240 animals, going back to only 12 founders. In a cooperate international operation Mhorr gazelles of European zoo populations were successfully reintroduced to national parks and nature reserves in Morocco and Tunisia in the years 1990/1992. The genetical and ecological prerequisites as well as the breeding aspects are discussed.


Work productivity among adults with varied Body Mass Index: Results from a Canadian population-based survey.
The relationship between Body Mass Index (BMI) and work productivity, including absenteeism and presenteeism remains unclear. The objective of this study was to examine work productivity among adults with varied BMI using population-based data. Data source was the 2009-2010 Canadian Community Health Survey. The outcomes reflected work absence (absenteeism) and reduced activities at work (presenteeism). The key explanatory variable was BMI in six categories. Logistic regressions were used to measure the association between outcome and explanatory variables adjusting for potential confounders. The sample consisted of 56,971 respondents ranging in age from 20 to 69 years. Relative to normal BMI, the odds of absenteeism were higher for those in the obesity class III (OR=1.60, 95% CI: 1.39; 1.83). Presenteeism was weakly associated with all obesity categories (OR=1.49, 95% CI: 1.38; 1.61, for obesity class I). Overweight was marginally associated with absenteeism and presenteeism. Underweight was inversely associated with absenteeism. This study found that obesity is an independent risk factor for reduced work productivity. Both absenteeism and presenteeism were associated with obesity. However, being overweight was weakly associated with work productivity.


Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000.
In the United States, young people aged 15-24 represent 25% of the sexually experienced population. However, the incidence and prevalence of sexually transmitted diseases (STDs) among this age-group are unknown. Data from a variety of sources were used to estimate the incidence and prevalence of STDs among 15-24-year-olds in the United States in 2000. The quality and reliability of the estimates were categorized as good, fair or poor, depending on the quality of the data source. Approximately 18.9 million new cases of STD occurred in 2000, of which 9.1 million (48%) were among persons aged 15-24. Three STDs (human papillomavirus, trichomoniasis and chlamydia) accounted for 88% of all new cases of STD among 15-24-year-olds. These estimates emphasize the toll that STDs have on American youth. More representative data are needed to help monitor efforts at lowering the burden of these infections.


Placental transfer of a large angiotensin fragment in the guinea pig.
Angiotensin II (AII) levels are usually higher in the fetal than in the maternal circulations. Radioiodinated AII has been used to establish whether or not this hormone crosses the placenta from the fetus to the mother in the pregnant guinea pig. No intact radioiodinated AII was found to have crossed in any of 13 experiments. A single radioiodinated AII fragment was found in 10 of these experiments. This ran as (des-(Asp1 Arg2 Val3)) in one solvent, but this could not be confirmed when a different solvent was used. The results support the hypothesis, previously based on indirect evidence, that AII does not cross the placenta.


Successful autologous peripheral blood stem cell transplantation with a double-conditioning regimen for recurrent hepatoblastoma after liver transplantation.
A four-yr-old boy developed a solitary metastasis nine months after living-related liver transplantation for unresectable hepatoblastoma. After resection of the metastatic lesion, he received an auto-PBSCT with a double-conditioning regimen consisting of melphalan and thiotepa. Auto-PBSCT could be safely performed without any serious regimen-related toxicity or infection. However, transient cessation of tacrolimus during myelosuppression resulted in graft rejection of the liver just after hematological engraftment, but rejection was resolved by tacrolimus and methylprednisolone. The patient is alive and free from disease two yr after auto-PBSCT without any signs of graft rejection. High-dose chemotherapy using this conditioning regimen may be feasible for recurrent hepatoblastoma after liver transplantation in terms of safety and anti-tumor activity.


Radiation Dose during Transarterial Radioembolization: A Dosimetric Comparison of Cone-Beam CT and Angio-CT Technologies.
To evaluate the radiation dose differences for intraprocedural computed tomography (CT) imaging between cone-beam CT and angio-CT acquired during transarterial radioembolization (TARE) therapies for hepatocellular carcinoma. A retrospective cohort of 22 patients who underwent 23 TARE procedures were selected. Patients were imaged in both cone-beam CT and angio-CT rooms as a part of their conventional treatment plan. Effective dose contributions from individual CT acquisitions as well as the cumulative dose contributions from procedural 3D imaging were evaluated. Angiography dose contributions were omitted. Cone-beam CT images were acquired on a C-arm Philips Allura system. Effective doses were evaluated by coupling previously published conversion factors (effective dose per dose-area product) to patient's dose-area product meter readings after the procedure. Angio-CT images were acquired on a hybrid Canon Infinix-i Aquilion PRIME system. Effective doses from angio-CT scans were estimated using Radimetrics. Comparisons of a single patient's dose differential between the 2 technologies were made. The mean effective dose from a single CT scan was 6.42 mSv and 5.99 mSv in the cone-beam CT room and the angio-CT room, respectively (P = .3224), despite the greater field of view and average craniocaudal scan coverage in angio-CT. The mean effective dose summed across all CTs in a procedure was 12.89 mSv and 34.35 mSv in the cone-beam CT room and the angio-CT room, respectively (P = .0018). The mean effective dose per CT scan is comparable between cone-beam CT and angio-CT when considered in direct comparison for a single patient.


Emergency cesarean delivery: special precautions.
An emergent cesarean delivery is performed to immediately intervene to improve maternal or fetal outcome for such indications as fetal distress, prolapsed cord, maternal hemorrhage from previa or trauma, uterine rupture, and complete placental abruption. It is paramount to reduce morbidity and mortality by preparing health care providers for special precautions.


Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2.
P2 membrane receptors for nucleotides represent significant targets for experimental pharmacology and drug research. In earlier publications, we have shown that Reactive Blue 2 (RB 2), one of the most widely used P2-receptor antagonists, displays only moderate affinity and does not discriminate between native P2X- and P2Y-receptor subtypes. In the present study we have pharmacologically evaluated a series of 15 synthesized and re-evaluated four commercially obtained and chromatographically purified RB 2 type anthraquinone derivatives on contractions of the rat vas deferens (RVD) elicited by alpha,beta-methylene ATP (alpha,beta-meATP), mediated by P2X1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic pi-electron systems, hydrogen bonds with nitrogen as donor and acceptor atoms, and, particularly, position, conformational distance and number of anionic sulfonate groups are of great importance for the blockade of the two native P2-receptor subtypes. We have also identified novel, for the most part reversible antagonists that bind with higher affinity and improved subtype selectivity in comparison to RB 2. In particular, 1-amino-4-{4-[4-chloro-6-(2-sulfonatophenylamino)-[1,3,5]triazine-2-ylamino]-2-sulfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y1-like-receptors of the GPTC reported so far (IC50=4.6 nM). It is significantly less potent as reversible antagonist at the P2X1-receptors of the RVD (IC50=2.8 microM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations.


Effect of excessive gestational weight gain before and after 28 weeks on trial of labor after cesarean stratified by pre-pregnancy body mass index: a retrospective cohort study.
This study aimed to assess the effect of excessive gestational weight gain (GWG) before and after 28 weeks on the mode of delivery in women who attempted a trial of labor after cesarean (TOLAC), stratified by pre-pregnancy BMI. A retrospective analysis of the outcomes of eligible women who attempted trial of labor after cesarean (TOLAC) in a Chinese hospital from January 2016 to October 2022 was performed. GWG before and after 28 weeks was categorized as 'excessive' or 'non-excessive' based on the guideline of Institute of Medicine (IOM). Multivariable logistic regression analyses were used to estimate the effect of excessive GWG before and after 28 weeks on mode of delivery in women who underwent TOLAC, stratified by pre-pregnancy BMI. Of the 512 women who underwent term trial of labor, 71.1% achieved a vaginal birth. No correlation was found between excessive GWG before 28 weeks and the rate of vaginal birth after cesarean (VBAC). Among women with or without excessive GWG before 28 weeks, excessive GWG after 28 weeks was significantly associated with a reduced rate of VBAC. When stratified by pre-pregnancy BMI, women who had excessive gestational weight gain after 28 weeks gestation had lower rates of VBAC than those who did not, regardless of being underweight, normal or overweight (aOR 0.23, 95% CI 0.06-0.88; aOR 0.42, 95% CI 0.25, 0.70; and aOR 0.12, 95% CI 0.04-0.36; respectively). Excessive weight gain after 28 weeks of pregnancy was related to decreased rates of VBAC, irrespective of pre-pregnancy weight status and weight gain before 28 weeks.


Immunohistochemical localization of hepatitis B surface antigen and hepatitis B core antigen in tissue sections. A source of false positive staining.
The occurrence of apparent false positive immunoperoxidase staining for hepatitis B surface antigen (HBsAg) led to the evaluation of several commercial antisera for usefulness in the diagnosis of hepatitis B by immunohistochemistry. One commercial antibody to hepatitis B core antigen (HBcAg) was tested and found to give sensitive and specific staining, with only a few false negatives and no false positives. Of three antibodies to HBsAg, one gave good staining results that were consistent with serologic data; one had many false positive stains due to contaminating antibodies to plasma proteins; and one (a monoclonal antibody) had many false negatives, probably due to its restricted antigenic specificity. Diagnosticians should be aware of the problems with false positive and false negative immunohistochemical stains. False positives in particular can be a significant problem, causing frequent misdiagnosis of hepatitis B.


[Anti-D sensitizations in the Leipzig District recorded in 1980 and 1981 and their relation to IgG-anti-D(Rh0) immunoprophylaxis].
In 173 female anti-D-carriers the course of sensibilization found were analysed with respect to Rh-immunoprophylaxis with IgG-anti-D(Rh0). By subdividing into groups before and after introducing Rh-immunoprophylaxis since 1971 the consequences of anti-D-sensibilization are pointed out after Rh-incompatible transfusions, with neglect of treatment and with legally not required treatment in Rh-negative female patients. In addition, failures are analysed. Further problems are presented by the group of prenatal transplacental haemorrhages appearing as late sensibilizations in pregnancy and raising discussions at the time of immunoprophylaxis. Those examples of the course of immunization being particularly evident are represented as descriptors in the form of "sensibilizing chains".


Life events, genetic susceptibility, and smoking among adolescents.
Although stressful life events during adolescence are associated with the adoption of unhealthy behaviors such as smoking, both social circumstances and physical traits can moderate the relationship. This study builds on the stress paradigm and gene-environment approach to social behavior by examining how a polymorphism in the serotonin transporter gene 5-HTTLPR moderates the effect of life events on adolescent smoking. Tests of interaction hypotheses use data from the Family Transitions Project, a longitudinal study of 7th graders followed for 5years. A sibling-pair design with separate models for the gender composition of pairs (brothers, sisters, or brother/sister) controls for unmeasured family background. The results show that negative life events are significantly and positively associated with smoking. Among brother pairs but not other pairs, the results provide evidence of gene-environment interaction by showing that life events more strongly influence smoking behavior for those with more copies of the 5-HTTLPR S allele.


Ultrasound mammography in the management of breast cancer.
In this centre, ultrasound mammography has been shown to be more accurate in elucidating the nature of palpable breast lesions than X-ray mammography. A prospective study was devised to determine whether this accuracy could be translated into improved management of patients with breast carcinoma. A total of 223 patients with palpable breast masses were assessed by clinical examination, imaging (X-ray and ultrasound mammography) and aspiration cytology. Each was scored on a five-point scale and treatment was planned according to the total score. According to the protocol, an adequate total score would permit definitive surgery avoiding frozen section. By using sonography rather than radiology, the number of correct diagnoses could be improved by 25 per cent. This was because the greater sensitivity of ultrasound (92.8 per cent) compared to X-ray mammography (82.5 per cent) was reflected in a higher total score, which was sufficient to allow definitive surgical treatment without prior histological confirmation of diagnosis.


Remodeling protein complexes: insights from the AAA+ unfoldase ClpX and Mu transposase.
Multiprotein complexes in the cell are dynamic entities that are constantly undergoing changes in subunit composition and conformation to carry out their functions. The protein-DNA complex that promotes recombination of the bacteriophage Mu is a prime example of a complex that must undergo specific changes to carry out its function. The Clp/Hsp100 family of AAA+ ATPases plays a critical role in mediating such changes. The Clp/Hsp100 unfolding enzymes have been extensively studied for the roles they play in protein degradation. However, degradation is not the only fate for proteins that come in contact with the ATP-dependent unfolding enzymes. The Clp/Hsp100 enzymes induce structural changes in their substrates. These structural changes, which we refer to as "remodeling", ultimately change the biological activity of the substrate. These biological changes include activation, inactivation (not associated with degradation), and relocation within the cell. Analysis of the interaction between Escherichia coli ClpX unfoldase and the Mu recombination complex, has provided molecular insight into the mechanisms of protein remodeling. We discuss the key mechanistic features of the remodeling reactions promoted by ClpX and possible implications of these findings for other biological reactions.


X-ray diffraction imaging with the Multiple Inverse Fan Beam topology: principles, performance and potential for security screening.
The steadily increasing number of explosive threat classes, including home-made explosives (HMEs), liquids, amorphous and gels (LAGs), is forcing up the false-alarm rates of security screening equipment. This development can best be countered by increasing the number of features available for classification. X-ray diffraction intrinsically offers multiple features for both solid and LAGs explosive detection, and is thus becoming increasingly important for false-alarm and cost reduction in both carry-on and checked baggage security screening. Following a brief introduction to X-ray diffraction imaging (XDI), which synthesizes in a single modality the image-forming and material-analysis capabilities of X-rays, the Multiple Inverse Fan Beam (MIFB) XDI topology is described. Physical relationships obtaining in such MIFB XDI components as the radiation source, collimators and room-temperature detectors are presented with experimental performances that have been achieved. Representative X-ray diffraction profiles of threat substances measured with a laboratory MIFB XDI system are displayed. The performance of Next-Generation (MIFB) XDI relative to that of the 2nd Generation XRD 3500TM screener (Morpho Detection Germany GmbH) is assessed. The potential of MIFB XDI, both for reducing the exorbitant cost of false alarms in hold baggage screening (HBS), as well as for combining "in situ" liquid and solid explosive detection in carry-on luggage screening is outlined.


Papaverine testing of impotent patients following nerve-sparing radical prostatectomy.
To investigate the etiology of impotence following nerve-sparing radical retropubic prostatectomy we performed papaverine testing on 23 patients who did not regain erections sufficient for vaginal penetration. Intervals from surgery to testing ranged from 3 to 30 months, with an average of 9 months. All patients achieved some degree of tumescence. In response to intracavernous papaverine injection only 1 patient (5 per cent) obtained an erection equivalent to the preoperative state. Of 18 patients who were fully potent preoperatively 8 (44 per cent) achieved an erection less than normal but judged to be sufficient for intercourse by the examining physician. Twelve patients, including 2 who were not fully potent preoperatively, had erections of poor quality insufficient for vaginal penetration. The results suggest that in most of these patients postoperative erectile dysfunction is predominantly vasculogenic in origin. Thus, factors other than injury to the neurovascular bundles may be responsible for postoperative impotence.


Use of Contrast-Enhanced Ultrasound to Determine Thoracic Duct Patency.
The aim of this study was to determine the feasibility of using contrast-enhanced ultrasound (CEUS) evaluation to determine thoracic duct (TD) outlet patency. Nine patients referred for lymphatic imaging and intervention underwent percutaneous intranodal ultrasound contrast injection and conventional lymphangiography (CL). Eight of 9 patients had a patent TD by CEUS and CL. One patient did not have a patent TD. There was 100% agreement between CEUS and CL. These results suggest that CEUS is an imaging modality that might be as accurate as CL in determining TD patency.


Pain improvement and reoperation rate after full-endoscopic decompression for lateral recess stenosis: a 10-year follow-up.
To share long-term clinical outcomes and our experience with full-endoscopic interlaminar decompression (FEI) for lateral recess stenosis (LRS). We included all patients who underwent FEI for LRS from 2009 to 2013. VAS for leg pain, ODI, neurological findings, radiographic findings, and complications were analyzed at one week, one month, three months, and one year postoperation. The telephone interview for local patients with simple questions was done approximately ten years after the operation. International patients receive an email with the same questionnaire as local patients during the same follow-up period. One hundred and twenty-nine patients underwent FEI for LRS with complete data during 2009-2013. Most of the patients (70.54%) had LRS radiculopathy for less than one year, mainly L4-5 (89.92%), followed by L5-S1 (17.83%). Early outcomes three months after surgery showed that most patients (93.02%) reported significant pain relief, and 70.54% reported no pain at their ODI scores were significantly reduced from 34.35 to 20.32% (p = 0.0052). In contrast, the mean VAS for leg pain decreased substantially by 3.77 points (p < 0.0001). There were no severe complications. At ten years of follow-up, 62 patients responded to the phone call or email. 69.35% of the patients reported having little or no back or leg pain, did not receive any further lumbar surgery, and were still satisfied with the result of the surgery. There were six patients (8.06%) who underwent reoperation. FEI for LRS was satisfactory at 93.02%, with a low complication rate during the early follow-up period. Its effect seems to decline slightly in the long term at a 10-year follow-up. 8.06% of the patients subsequently underwent reoperation.


Prolactin and estradiol increase striatal dopamine receptor density in intact, castrated and hypophysectomized rats.
1. Ovariectomized female or intact male rats were implanted with three adenohypophyses under the kidney capsule or treated with 17 beta-estradiol (10 micrograms twice daily) for 2 weeks. 2. In animals of both sexes, the pituitary-implanted and estradiol-treated rats had elevated plasma prolactin levels and had increased levels of striatal dopamine receptors. 3. We next investigated the possibility of an indirect action of estradiol via prolactin using hypophysectomized female rats (hypox) treated with 17 beta-estradiol or ovine prolactin (500 micrograms, twice daily) for 5 days. 4. Striatal dopamine receptor concentration was lower in hypox animals as compared to ovariectomized (85%, p less than 0.05) or intact female rats at random stage of the estrous cycle (76%, p less than 0.05) while the affinity (KD) of [3H]spiperone for these dopaminergic sites remained unchanged. 5. Treatment with estradiol or prolactin increased the level of striatal dopamine receptors (HYPOX + estradiol: 144% vs HYPOX, p less than 0.05; HYPOX + prolactin: 147% vs HYPOX, p less than 0.05). 6. These results indicate that high prolactin levels induced by pituitary implants or by injections of ovine prolactin lead, as observed with chronic estradiol treatment, to an increased density of striatal dopamine receptors. However, the effect of estradiol may not be explained exclusively by increased prolactin levels since the supersensitivity is also observed in hypophysectomized animals.


Predictors of negative symptoms in the chronic phase of schizophrenia: A cross-sectional study.
This study was designed to investigate the relationship between negative symptoms and key indicators for long-term hospital stays among inpatients with schizophrenia. A further aim was to elucidate the clinical determinants of negative symptoms. The following were used as index factors: age, duration of illness, duration of hospitalization, age at onset, years of education, smoking status, body mass index, concentrations of serum triglycerides, total cholesterol, uric acid, QTc interval duration from electrocardiography, dose equivalents of antipsychotic and anticholinergic agents, neurocognitive function, drug-induced extrapyramidal symptoms, involuntary movements, and psychiatric symptoms. Spearman's rank correlation coefficients were calculated and regression analyses were performed to examine associations between these factors and negative symptoms. Positive symptoms correlated positively with negative symptoms as rated on the Brief Psychiatric Rating Scale. Age at onset correlated negatively with negative symptoms. Multiple regression analysis showed that dose equivalents of atypical antipsychotics and positive symptoms predicted negative symptoms. Increasing our understanding of these predictors as key indicators of the severity of negative symptoms may aid in the reconsideration of therapeutic programs for chronic schizophrenia.


Improving lung cancer prognosis assessment by incorporating synthetic minority oversampling technique and score fusion method.
This study aims to investigate the potential to improve lung cancer recurrence risk prediction performance for stage I NSCLS patients by integrating oversampling, feature selection, and score fusion techniques and develop an optimal prediction model. A dataset involving 94 early stage lung cancer patients was retrospectively assembled, which includes CT images, nine clinical and biological (CB) markers, and outcome of 3-yr disease-free survival (DFS) after surgery. Among the 94 patients, 74 remained DFS and 20 had cancer recurrence. Applying a computer-aided detection scheme, tumors were segmented from the CT images and 35 quantitative image (QI) features were initially computed. Two normalized Gaussian radial basis function network (RBFN) based classifiers were built based on QI features and CB markers separately. To improve prediction performance, the authors applied a synthetic minority oversampling technique (SMOTE) and a BestFirst based feature selection method to optimize the classifiers and also tested fusion methods to combine QI and CB based prediction results. Using a leave-one-case-out cross-validation (K-fold cross-validation) method, the computed areas under a receiver operating characteristic curve (AUCs) were 0.716 ± 0.071 and 0.642 ± 0.061, when using the QI and CB based classifiers, respectively. By fusion of the scores generated by the two classifiers, AUC significantly increased to 0.859 ± 0.052 (p < 0.05) with an overall prediction accuracy of 89.4%. This study demonstrated the feasibility of improving prediction performance by integrating SMOTE, feature selection, and score fusion techniques. Combining QI features and CB markers and performing SMOTE prior to feature selection in classifier training enabled RBFN based classifier to yield improved prediction accuracy.


A psychocutaneous profile of psoriasis patients who are stress reactors. A study of 127 patients.
Psoriasis is a chronic, relapsing, cutaneous condition with a 1%-2% prevalence in the general population. About 40% of psoriatics report that psychosocial stress significantly exacerbates their condition. However, the clinical characteristics of the subgroup of psoriatic patients who are stress reactors have not been delineated. At a practical clinical level it is therefore difficult to implement specific psychosocial treatments among the psoriatic population. In this study, we compared the psychocutaneous characteristics of patients who reported that stress exacerbated their psoriasis, i.e., the high stress reactors (N = 64) to the subgroup who reported no significant association between stress and their psoriasis, i.e., the low stress reactors (N = 63). The high stress reactors had more disfiguring disease clinically (p less than 0.02); psychologically they tended to rely more upon the approval of others (p less than 0.05) and experienced more psoriasis-related daily stress (p less than 0.005). The high stress reactors also reported more flare-ups of their psoriasis during the 6 months prior to admission (p less than 0.05). We have shown that the high stress reactors can be clinically delineated from the low stress reactors. Certain psychosocial interventions will most likely decrease the morbidity associated with psoriasis among the high stress reactors, and may possibly even result in a decline in the number of major flare-ups of the psoriasis.


Biphasic effects of some dopamine agonists on striatal acetylcholine concentrations.
Since the reduction of striatal dopaminergic transmission decreases striatal acetylcholine (ACh) levels due to disinhibition of the respective neurons, such an effect might be expected after selective stimulation of dopamine (DA) autoreceptors. The effects of a number of DA agonists, including the purportedly selective presynaptic agents 3-PPP and TL 99, on striatal ACh levels were investigated over a wide dose range. Apomorphine and 3-PPP decreased ACh levels in a lower dose range (0.01-0.03 mg/kg s.c. and 0.2-1 mg/kg s.c., resp.) TL 99 showed a significant, but much smaller effect (0.1-0.3 mg/kg s.c.), whereas piribedil and bromocriptine only increased ACh. However, 3-PPP (at 3 mg/kg and above) and TL 99 (at 3 mg/kg) increased ACh in much the same way as did conventional DA agonists. These results suggest (a) that pre- and postsynaptic DA receptors are distinct in a functionally relevant manner, and (b) that 3-PPP and TL 99 possess postsynaptic effects on DA receptors associated with cholinergic neurons. Since 3-PPP does not elicit stereo sterotypes in spite of evidence for an involvement of cholinergic neurons in the mediation of this behaviour it might be assumed that it acts on other postsynaptic DA receptors than does apomorphine. Moreover, it seems possible that the two types of DA receptors are located on two different types of cholinergic neurons with different functions.


Author Correction: The importance of Antarctic krill in biogeochemical cycles.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.