The effects of proteins and medium-chain fatty acids from milk on body composition, insulin sensitivity and blood pressure in abdominally obese adults.
To investigate whether intake of whey protein and butter naturally enriched in medium-chain fatty acids (MC-SFAs) (C6-C12) affected body composition, insulin sensitivity, blood pressure (BP) and plasma cholesterol concentrations. A 12-week randomised, double-blinded, intervention study was completed in 52 abdominally obese adults. Subjects were assigned to one of four dietary supplementations: 63 g per day of milk fat with either high- (8.5 g per day) or low-MC-SFA (6.9 g per day) content combined with 60 g per day of whey or casein.We examined changes in the body composition by dual-energy X-ray absorption scan, insulin sensitivity using homoeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda index, and diurnal BP and plasma cholesterol concentrations. Two-factor analysis of variance was used to examine the impact of MC-SFA content and protein type. We observed that lean body mass increased by 981 g (95% confidence interval (CI): 248-1713; P=0.010) after high-MC-SFA compared with low-MC-SFA supplementation. Concomitantly, total body-fat percentage increased by 0.70 percentage points (95% CI: 0.10-1.31; P=0.024) after intake of low-MC-SFA butter compared with intake of high-MC-SFA butter. Both changes were independent of protein type (P=0.96 and P=0.99, respectively). We found no difference in HOMA-IR, Matsuda index, diurnal BP or plasma cholesterol concentrations related to MC-SFA content or protein type. Enhanced intake of MC-SFA increased the lean body mass and caused a significantly lower total body-fat percentage compared with lower intake of MC-SFA. Consequently, the composition of dairy fat should be considered when evaluating the impact of dairy products on body composition.


[Gas permeable scleral lenses as a conservative treatment option for extreme corneal ectasias and severe dry eye].
Due to their exclusive scleral contact zone, non-ventilated gas permeable scleral contact lenses can be used to correct extreme keratectasia, even if corneal fitted contact lenses failed previously. As the gap between the scleral lens and the cornea is filled with fluid substitutes, they also can be used for patients with severe aqueous-deficient dry eyes. PATIENTS, MATERIAL AND METHOD: Scleral lens fitting was attempted in 13 eyes (9 patients, group I) of patients with extreme corneal ectasia and 9 eyes (5 patients, group II) with severe ocular surface disease. Best corrected visual acuity, keratometry, Schirmer's test, foreign body sensation, and total daily lens wearing time were recorded prior to and after scleral lens fitting. Scleral lenses were successfully fitted and used on a long-term basis in 6 of 13 eyes (4 patients) of group I and 4 of 9 eyes of group II. In 9 eyes visual acuity increased by at least 2 lines, but long-term lens wear was not possible due to severe foreign body sensation or fornix shortening. Modern gas permeable scleral lenses can successfully be used for nonsurgical rehabilitation of severe corneal ectasia and dry eyes.


Some aquatic fungi of Hyphomycetes on tree leaves.
The presence of the aquatic Hyphomycetes in the rain water draining from the leaves of 17 species of trees (8 gymnospermous species and 9 angiospermous species) were studied. Evolution of 18 aquatic Hyphomycetes species was observed in the water draining from trees. The of most frequently encountered species of aquatic fungi Hyphomycetes in rain water draining from trees were Anguillospora pseudolongissima, Heliscus lugdunensis and Vargamyces aquaticus.


Combining information to estimate adherence in studies of pre-exposure prophylaxis for HIV prevention: Application to HPTN 067.
In trials of oral HIV pre-exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self-report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non-adherent subgroups may yield important insights into real-world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self-report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women.


Decreased expression of intestinal P-glycoprotein increases the analgesic effects of oral morphine in a streptozotocin-induced diabetic mouse model.
Morphine is one of the strongest analgesics and is commonly used for the treatment of chronic pain. The pharmacokinetic properties of morphine are, in part, modulated by P-glycoprotein (P-gp). We previously reported that intestinal P-gp expression levels are influenced via the activation of inducible nitric oxide synthase (iNOS) in streptozotocin (STZ)-induced diabetic mice. Herein, we examine the analgesic effects of orally administered morphine and its pharmacokinetic properties under diabetic conditions, specifically we focusing on the involvement of intestinal P-gp in a type 1 diabetic mouse model. We assessed the analgesic effect of morphine using the tail-flick test. Serum and brain morphine levels were determined using a HPLC-ECD system. Oral morphine analgesic effects and serum and brain morphine content were significantly increased 9 days after STZ administration. The increase in the analgesic effects of morphine, as well as serum and brain morphine content, was suppressed by aminoguanidine, a specific iNOS inhibitor. Conversely, there were no changes in the analgesic effects obtained with subcutaneous morphine in STZ-treated mice. Our findings suggest that the analgesic effects of oral morphine are dependent on intestinal P-gp expression, and this may be one of the reasons that it is difficult to obtain stable pharmacological effects of morphine in diabetic patients.


[Nonsteroidal anti-inflammatory drugs in the treatment of anterior uveitis associated with spondyloarthritis].
Anterior uveitis (AU) is one of the common extraskeletal manifestations of spondyloarthritis (SpA). The course of AU in patients with SpA is characterized by frequent relapses. The article considers the question of local and systemic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment and prevention of SpA-associated uveitis exacerbations.


Chronic eosinophilic leukemia: successful treatment with an unrelated bone marrow transplantation.
The optimal treatment of eosinophilic leukemia is still uncertain. We report the successful treatment of a 21-year-old patient with eosinophilic leukemia, without cytogenetic abnormalities, by bone marrow transplantation from an unrelated donor. The conditioning regimen for the transplantation consisted of fractionated total body irradiation and cyclophosphamide. Acute GVHD, grade I, post-transplantation was successfully treated. No other severe complications occured. The patient is alive in complete remission 21 months after unrelated bone marrow transplantation.


Functional identification of rat atypical beta-adrenoceptors by the first beta 3-selective antagonists, aryloxypropanolaminotetralins.
1. We have assessed the relative abilities of compounds belonging to the new aryloxypropanolaminotetralin (APAT) class and of the reference beta-adrenoceptor-blocking agent, alprenolol, to antagonize functional responses in vitro and in vivo involving atypical (beta 3) or conventional (beta 1 and beta 2) beta-adrenoceptors. 2. The range of pA2 values for three representative APATs against inhibition of spontaneous motility in the rat isolated colon by the selective beta 3-adrenoceptor agonist, SR 58611A (8.1-8.8), was well above similarly calculated values for non-competitive antagonism of guinea-pig trachea relaxation by salbutamol (beta 2, 6.5-6.9) and the atrial chronotropic response by isoprenaline (beta 1, 6.7-7.3). Alprenolol, however, was substantially more potent in antagonizing atrial (pA2, 8.2) and tracheal (pA2, 8.9) responses than SR 58611A mediated inhibition of colonic motility (pA2, 6.8). 3. Several APAT isomers with different configurations at the chiral carbons, when tested on isolated organs, presented stringent stereochemical requirements for beta 3-selectivity, including high antagonist potency-ratios between active and inactive enantiomers. 4. In vivo, the inhibition of colonic motility and the thermogenic response of brown adipose tissue elicited in rats by the selective beta 3-adrenoceptor agonists SR 58611A and BRL 37344 respectively were substantially diminished by the representative APAT, SR 59230A, at oral doses (< or = 5 mg kg-1) well below those half maximally effective (ID50) for preventing beta 1-(isoprenaline tachycardia > or = 80 mg kg-1) or beta 2-(salbutamol bronchodilatation, 44 mg kg-1) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative beta 3-responses. 5. These findings support APATs as the first potent, orally effective selective antagonists at beta 3-adrenoceptors, and provide final unambiguous evidence that beta 3-adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.


Screening programs to identify children at risk for diabetes mellitus: psychological impact on children and parents.
Screening programs to identify persons atrisk for diabetes mellitus (DM), before disease onset, are considered essential to understanding the natural history of the disease and for prevention program development. However, screening programs are complicated by imprecise markers of disease risk, the absence of a known effective prevention method, the use of children, and a wide variety of psychological, social, and educational challenges. Research relevant to four issues is presented: (1) parent and child anxiety in response to at-risk notification as well as how participants cope with this news; (2) accuracy of mothers' understanding of their babies' risk status; (3) predictors of participant recruitment and retention in longitudinal studies of this type; and (4) protocol compliance in prevention trials for type 1 DM. Integration of behavioral research into screening and prevention trials would help address the ethical concerns raised by such trials and improve their scientific quality.


Successful discontinuation of immunoglobulin G replacement at age 10 in a patient with immunoglobulin G2 deficiency.
Immunoglobulin G2 deficiency that persists beyond the age of 6 years is likely to be permanent. We report on a young Japanese female, diagnosed as having immunoglobulin G2 deficiency and low anti-pneumococcal immunoglobulin G2 antibody levels when 3 years old, with a subsequent medical history of frequent respiratory infections and asthma. Monthly intravenous immunoglobulin replacement therapy was started at 4 years of age. After 8 years of age, an anti-pneumococcal immunoglobulin G2 trough level could be maintained with administration intervals longer than 6 weeks, and after 9 years and 10 months of age, therapy was discontinued. The frequency of hospital admissions was reduced by the introduction of the replacement therapy (from 8.4 times/year before the introduction to 1.1 times/year during the therapy). The patient was also able to discontinue daily medications for asthma, and serum immunoglobulin G2 was maintained at a normal level even after the cessation of replacement therapy. Termination of immunoglobulin replacement therapy in a patient with a symptomatic immunoglobulin G2 deficiency is possible, even for a child older than 6 years.


Rescue of germ cells in dnd crispant embryos opens the possibility to produce inherited sterility in Atlantic salmon.
Genetic introgression of escaped farmed Atlantic salmon (Salmo salar) into wild populations is a major environmental concern for the salmon aquaculture industry. Using sterile fish in commercial aquaculture operations is, therefore, a sustainable strategy for bio-containment. So far, the only commercially used methodology for producing sterile fish is triploidization. However, triploid fish are less robust. A novel approach in which to achieve sterility is to produce germ cell-free salmon, which can be accomplished by knocking out the dead-end (dnd) gene using CRISPR-Cas9. The lack of germ cells in the resulting dnd crispants, thus, prevents reproduction and inhibits subsequent large-scale production of sterile fish. Here, we report a rescue approach for producing germ cells in Atlantic salmon dnd crispants. To achieve this, we co-injected the wild-type (wt) variant of salmon dnd mRNA together with CRISPR-Cas9 constructs targeting dnd into 1-cell stage embryos. We found that rescued one-year-old fish contained germ cells, type A spermatogonia in males and previtellogenic primary oocytes in females. The method presented here opens a possibility for large-scale production of germ-cell free Atlantic salmon offspring through the genetically sterile broodstock which can pass the sterility trait on the next generation.


A comparison of virus-associated and multi-trigger wheeze in school children.
To examine differences between virus-associated wheeze and wheeze associated with other triggers (multi-trigger wheeze) in elementary school children, we performed a cross-sectional school-based questionnaire study of 5,998 children mainly 7 to 12 years of age, with outliers 6 and 13 years of age. Using parent-completed questionnaires, we identified 522 children who wheezed only during upper respiratory tract infections (virus-associated wheeze), 1,186 children who wheezed on other occasions (multi-trigger wheeze), and 4,290 children with no wheeze. In comparison with children who had multi-trigger wheeze, children with virus-associated wheeze were more likely to be male, to be younger, and to have less frequent wheezy episodes. They were less likely to have night cough, shortness of breath or chest tightness, to have a personal or parental history of atopic disorders, to have a diagnosis of asthma, or to be receiving asthma treatment. Both types of wheeze were associated with social deprivation, a relationship that persisted after controlling for family smoking. Virus-associated wheeze is a common but diminishing problem in this age group, and the differences between virus-associated wheeze and multi-trigger wheeze already noted in pre-school children persist in this older age group.


Concise review: harmonies played by microRNAs in cell fate reprogramming.
It is now well-established that somatic cells can be reprogrammed to alternative cell fates by ectopic coexpression of defined factors. Reprogramming technology has uncovered a huge plasticity besides gene regulatory networks (GRNs) of differentiated cell states. MicroRNAs (miRNAs), which are an integral part of GRNs, have recently emerged as a powerful reprogramming toolbox. They regulate numerous genes, thereby modulating virtually all cellular processes, including somatic cell reprogramming. Not only can miRNAs provide novel opportunities for interrogating mechanisms of induced pluripotency and direct lineage reprogramming but they also offer hope for the efficient creation of safe cell sources for regenerative medicine. In reviewing landmark roles of miRNAs in cell reprogramming, we offer suggestions for evolution of the reprogramming field.


Subcutaneous metastasis from recurrent basaloid squamous cell carcinoma of the esophagus.
Esophageal cancer is the 11th most common cause of cancer mortality in the United States. It is aggressive in nature and has an ability to spread rapidly through direct extension, lymphatic spread, or hematogenously. With an estimated incidence of 1%, cutaneous metastases from esophageal cancer are extremely rare. In this case study and review, we describe a case of recurrent esophageal basaloid squamous cell carcinoma presenting as multiple, rapidly progressing and tender subcutaneous nodules. A 69-year-old male with history of basaloid squamous cell carcinoma of the esophagus treated with concurrent chemoradiation, presented to his oncologist with complaints of a large, painful nodule at the nape of his neck approximately two years after completing treatment. On further examination, he was noted to have multiple, well circumscribed, solid, tender nodules on his abdominal wall along with a painful nodule on the pulp of his index finger. Histopathology from all sites revealed skin infiltration by high-grade invasive basaloid subtype of squamous cell carcinoma, similar to patient's prior known and treated primary esophageal cancer. Further imaging work up showed extensive metastatic disease involving lung, liver, and brain. Esophageal squamous cell carcinoma rarely metastasize to the skin. Subcutaneous nodules can be the first presentation of recurrent disease. The lesions are commonly confused with skin infections and treated inappropriately with antibiotics, leading to delay in diagnosis of recurrent disease. Early biopsy of suspicious lesions should be performed, especially in patients with history of cancer, such that prompt diagnosis and treatment can occur to maximize patient outcomes.


[Relation between cardiomyopathy and ventricular arrhythmias].
Ventricular arrhythmias (VA) with its relevant factors were studied in patients with cardiomyopathy and the relation between late potential (LP) and ventricular tachycardia (VT) was also evaluated. It is shown that the prevalence of VA was high in cardiomyopathy. However, its severity was not related to clinical symptoms, cardiac enlargement, cardiac function and level of plasma electrolytes. The relative risk and relative odds of LP positive were 7.33 and 20 times as high in patients with VT as in those without VT, respectively. The sensitivity, specificity, and accuracy of prediction to VT in LP positive patients were 66.2%, 90.9% and 80%, respectively. The patients with sustained VT and positive LP were more susceptible to sudden death. LP was useful to understand the mechanism and prognosis of VT.


Leukotriene D4 induces association of active RhoA with phospholipase C-gamma1 in intestinal epithelial cells.
It has been previously suggested that leukotriene-induced Ca2+ signalling is mediated through a Rho-dependent process, but neither direct activation of Rho nor a mechanism underlying such signalling has been reported. Accordingly, we used the Rhotekin binding assay to assess RhoA activation in intestinal epithelial cells and observed that RhoA was activated by leukotriene D4 (LTD4). We also found that, within 15 s, activation of RhoA by LTD4 led to an increased association of RhoA with G-protein betagamma (Gbetagamma) and phospholipase C-gamma1 (PLC-gamma1) in the plasma membrane, as evidenced by the results of co-immunoprecipitation, glutathione S-transferase (GST) pulldown assays, and confocal microscopy. Amounts of RhoA increased in both Gbeta and PLC-gamma1 immunoprecipitates within 15 s of LTD4 treatment. An interaction between RhoA, Gbetagamma and PLC-gamma1 is supported by our finding that a GST fusion protein of constitutively active RhoA (GST-RhoAV14) precipitated Gbetagamma and PLC-gamma1 from cell lysates in an agonist-dependent manner. Such an association is also substantiated by our confocal immunofluorescence results, which revealed that LTD4 induction increased co-localization of constitutively active RhoA and PLC-gamma1 to the plasma membrane of cells transfected with enhanced green fluorescent protein L63RhoA. Furthermore, microinjection of neutralizing RhoA antibodies, but not control antibodies, significantly reduced LTD4-induced Ca2+ mobilization. Our results are the first to demonstrate a LTD4-induced activation of RhoA and more importantly its association with PLC-gamma1, which are essential for the PLC-gamma1-mediated calcium mobilization.


Communication in collaborative discovery learning.
Constructivist approaches to learning focus on learning environments in which students have the opportunity to construct knowledge themselves, and negotiate this knowledge with others. Discovery learning and collaborative learning are examples of learning contexts that cater for knowledge construction processes. We introduce a computer-based learning environment in which the two forms of learning are implemented simultaneously. We focus on the interaction between discovery learning and collaborative learning. We aim to investigate which communicative activities are frequently used in the discovery learning process and which communicative and discovery activities co-occur. The study involved 21 pairs of 10th-grade students enrolled in pre-university education, ranging from 15 to 17 years of age. Participants worked in dyads on separate screens in a shared discovery learning environment. They communicated using a chat box. In order to find a possible relationship between communicative activities and discovery learning processes, correlational analysis and principal component analysis were performed. Significant relationships were found between communicative and discovery activities, as well as five factors combining the communicative process and the discovery learning processes. Communicative activities are performed most frequently during the activities in generating hypotheses, experimental design, and conclusion construction. Argumentation occurs less than expected, and is associated with the construction of conclusions, rather than generating hypotheses. Communicative activities co-occur with discovery activities most of the time, as we expected. Further research should concentrate on means to augment communicative and discovery activities that are related to positive learning outcomes.


A fourteen gene GBM prognostic signature identifies association of immune response pathway and mesenchymal subtype with high risk group.
Recent research on glioblastoma (GBM) has focused on deducing gene signatures predicting prognosis. The present study evaluated the mRNA expression of selected genes and correlated with outcome to arrive at a prognostic gene signature. Patients with GBM (n = 123) were prospectively recruited, treated with a uniform protocol and followed up. Expression of 175 genes in GBM tissue was determined using qRT-PCR. A supervised principal component analysis followed by derivation of gene signature was performed. Independent validation of the signature was done using TCGA data. Gene Ontology and KEGG pathway analysis was carried out among patients from TCGA cohort. A 14 gene signature was identified that predicted outcome in GBM. A weighted gene (WG) score was found to be an independent predictor of survival in multivariate analysis in the present cohort (HR = 2.507; B = 0.919; p<0.001) and in TCGA cohort. Risk stratification by standardized WG score classified patients into low and high risk predicting survival both in our cohort (p = <0.001) and TCGA cohort (p = 0.001). Pathway analysis using the most differentially regulated genes (n = 76) between the low and high risk groups revealed association of activated inflammatory/immune response pathways and mesenchymal subtype in the high risk group. We have identified a 14 gene expression signature that can predict survival in GBM patients. A network analysis revealed activation of inflammatory response pathway specifically in high risk group. These findings may have implications in understanding of gliomagenesis, development of targeted therapies and selection of high risk cancer patients for alternate adjuvant therapies.


High resolution imaging reveals heterogeneity in chromatin states between cells that is not inherited through cell division.
Genomes of eukaryotes exist as chromatin, and it is known that different chromatin states can influence gene regulation. Chromatin is not a static structure, but is known to be dynamic and vary between cells. In order to monitor the organisation of chromatin in live cells we have engineered fluorescent fusion proteins which recognize specific operator sequences to tag pairs of syntenic gene loci. The separation of these loci was then tracked in three dimensions over time using fluorescence microscopy. We established a work flow for measuring the distance between two fluorescently tagged, syntenic gene loci with a mean measurement error of 63 nm. In general, physical separation was observed to increase with increasing genomic separations. However, the extent to which chromatin is compressed varies for different genomic regions. No correlation was observed between compaction and the distribution of chromatin markers from genomic datasets or with contacts identified using capture based approaches. Variation in spatial separation was also observed within cells over time and between cells. Differences in the conformation of individual loci can persist for minutes in individual cells. Separation of reporter loci was found to be similar in related and unrelated daughter cell pairs. The directly observed physical separation of reporter loci in live cells is highly dynamic both over time and from cell to cell. However, consistent differences in separation are observed over some chromosomal regions that do not correlate with factors known to influence chromatin states. We conclude that as yet unidentified parameters influence chromatin configuration. We also find that while heterogeneity in chromatin states can be maintained for minutes between cells, it is not inherited through cell division. This may contribute to cell-to-cell transcriptional heterogeneity.


Esterification does not impair lutein bioavailability in humans.
Age-related macular degeneration (ARMD) is inversely associated with the accumulation of lutein + zeaxanthin in the macula, but higher lutein intakes are inconsistently related to reduced risk of ARMD in epidemiologic studies. Resolution of efficacy awaits clinical trials designed with knowledge of lutein supplement pharmacokinetics. Lutein bioavailability was determined for lutein diester and unesterified lutein formulations as they might be incorporated into dietary supplements. Healthy subjects (n = 18) consumed a single dose of each formulation (either 0.5 or 0.67 micro mol lutein/kg body, 10 and 8 subjects, respectively) in random order, and the appearance of free lutein + zeaxanthin was measured in serum from 0 to 408 h. Areas under the serum concentration x time curves (AUC), as a measure of bioavailability, were independent of gender, body mass index and lutein dose. The lutein diester formulation was 61.6% more bioavailable than the unesterified lutein formulation with higher mean AUC, maximum serum concentration and ascending slope (P < 0.05). The AUC was greater in 14 of 18 subjects when they consumed the lutein diester formulation. Comparison with data from previous studies suggested that dissolution was a greater limitation to bioavailability than lutein ester hydrolysis because an oil-solubilized unesterified lutein preparation, given at 0.5 micro mol/kg body, resulted in greater mean peak concentrations and AUC compared with either the unesterified or lutein diester formulations used in our study. In conclusion, the lutein diester formulation poses no impediment to lutein bioavailability at the doses tested, but formulation dissolution is an important factor in lutein bioavailability and should be evaluated before a supplement and dose are selected for use in clinical trials.


BRCA1 mutation testing for Japanese patients with ovarian cancer in breast cancer screening.
From February 1996 to April 1998, 2967 women received screening for breast cancer in the gynecologic ambulatory practice of the Hokkaido University Hospital. In 116 Japanese women with epithelial ovarian cancer, mutation analysis of BRCA1 exon 11 in genomic DNA was performed by the stop codon (SC) assay and DNA sequence analysis. Clinicopathological factors were also investigated in these patients. The aim of this study was to examine the advantages of performing BRCA1 mutation testing for ovarian cancer patients during breast cancer screening. We achieved a high detection rate (6.0%) of patients with germline mutations in BRCA1. The high frequencies of breast ovarian cancer syndrome, serous adenocarcinoma, high histological grades, advanced FIGO stages, and breast cancer as double cancer were found to be characteristic of ovarian cancer with germline mutations in BRCA1. These characteristics may assist physicians in selecting BRCA1 mutation testing for ovarian cancer patients. The mean age at diagnosis of ovarian cancer was 51.0 and 51.2 years in the groups with and without mutation, respectively, and no difference was found in age at diagnosis. All of the nine living female mutation carriers were offered the options of increased surveillance or prophylactic surgery, and all chose the former. We have performed breast cancer screening and/or ovarian cancer screening every 6 months for these carriers. This may allow another advantage in establishing a relationship of mutual trust with a patient from a series of responsible follow-ups.


Swift evaluation of electron density profiles obtained by the alkali beam emission spectroscopy technique using linearized reconstruction.
A method is presented for the swift reconstruction of electron density profiles measured by the alkali beam emission spectroscopy. It is based on the linearization of the governing rate equations and leads to a direct calculation for obtaining the profiles. The uncertainties of the measurement are incorporated into the problem through the utilization of Tikhonov regularization and the generalized least squares method. An approximation for the uncertainty of the reconstructed density data is calculated as well. The applicability of the method is tested against both simulated and real experimental results of the W7-X stellarator.


Perceived client and program moderators of successful therapeutic community treatment for drug addiction.
Research examining moderators of therapeutic community treatment outcomes has tended to emphasize the importance of length of stay in programs. To this extent the research literature implies a causal role for treatment in the determination of treatment outcomes. Using the Delphi technique, a panel of residents, staff members, and other drug treatment agency staff involved with the Odyssey House therapeutic community in Melbourne were surveyed regarding their perceptions of factors moderating successful treatment in this program. Examination of the perceptions of those involved with the delivery of therapeutic community treatment suggested a strong respect for the importance of client motivational factors in the determination of treatment outcomes. It is suggested that future research in this area could profitably focus on attempts to quantify the separate contribution of treatment and nontreatment factors in explaining treatment outcomes.


Purification and properties of a Ca(2+)-independent barbed-end actin filament capping protein, CapZ, from human polymorphonuclear leukocytes.
In human polymorphonuclear leukocytes (PMN), changes in the actin architecture are critical for the shape changes required for chemotaxis and phagocytosis. Barbed-end capping proteins are likely to regulate actin assembly in PMN. The previously identified barbed-end blocking proteins in PMN, gelsolin and CapG, require Ca(2+) to initiate capping of actin filaments. Because chemoattractants can stimulate PMN actin assembly by a calcium-independent signal transduction pathway, we sought to purify a calcium-independent barbed-end capping activity from PMN cytoplasmic extracts. A Ca(2+) -insensitive actin polymerization inhibitory activity was partially purified from human PMN [Southwick & Stossel (1981) J. Biol. Chem 256, 3030]. Using five column chromatography steps, we purified the protein to homogeneity as assessed by silver staining. Purification was associated with an increase in specific activity of greater than 40 X. Western blot analysis identified the protein as the nonmuscle isoform of the heterodimeric capping protein capZ. Human PMN capZ has an apparent disassociation constant of 3 nM for capping in the presence or absence of micromolar Ca(2+), as assessed by both pyrenylactin elongation and depolymerization assays. Similar to the activity reported for the actin polymerization inhibitor, activity of PMN capZ was inhibited by increasing the KC1 concentration from 0.1 M to 0.6 M. The capping function was also inhibited by phosphatidylinositol 4,5-bisphosphate (PIP(2)) micelles, with half-maximal inhibition occurring at 5.5 micrograms mL(-1). PMN capZ did not nucleate actin assembly, sequester actin monomers, or sever actin filaments. Quantitative Western blot analysis revealed that capZ levels corresponded to 0.7-1.0% of the total human PMN cytoplasmic protein. Given its abundance and high affinity for barbed filament ends, capZ is likely to play an important role in the calcium-independent regulation of actin filament assembly associated with PMN chemotaxis.


Therapeutic Efficacy of Temsirolimus in a Patient-derived Model of Metastatic Fibrolamellar Hepatocellular Carcinoma.
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents. Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin. PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity. Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.


Keratin 16 expression in epidermal melanocytes of normal human skin.
Although the prevailing dogma states that keratin filaments are the hallmark of keratinocytes and other epithelial cells, recent publications suggest that they may be expressed by a variety of normal and malignant cells of different embryonic origin. Keratin expression has been reported in fibroblasts and endothelial cells as well as in various sarcomas. Also, some human melanomas express keratins in addition to the traditional diagnostic markers of differentiation, such as S-100 and melanocyte-specific antigens. Many studies have shown that cultured cells obtained from various melanomas express keratin. Most recently, keratin expression has also been shown in cultured melanocytes of normal skin. We now report that normal human melanocytes in vivo express keratin 16 (K16) but not keratins 1, 5, 8, 10, 14, or even keratin 6, the type II partner that is normally expressed with K16 in keratinocytes. Similarly, melanocytes in vitro express K16 but not K6. Keratin 16 expression in vivo was present in basal melanocytes in specimens derived from donors (0-77 years) and from different anatomic locations, suggesting that keratin 16 is constitutively expressed by all melanocytes. It appears that keratin expression may be more prevalent than previously assumed, and that these cytoskeletal filaments may play important roles in tissues and cells other than epithelia.


Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Where will the drugs come from?
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic debilitating disease characterized by severe and disabling fatigue that fails to improve with rest; it is commonly accompanied by multifocal pain, as well as sleep disruption, and cognitive dysfunction. Even mild exertion can exacerbate symptoms. The prevalence of ME/CFS in the U.S. is estimated to be 0.5-1.5 % and is higher among females. Viral infection is an established trigger for the onset of ME/CFS symptoms, raising the possibility of an increase in ME/CFS prevalence resulting from the ongoing COVID-19 pandemic. Current treatments are largely palliative and limited to alleviating symptoms and addressing the psychological sequelae associated with long-term disability. While ME/CFS is characterized by broad heterogeneity, common features include immune dysregulation and mitochondrial dysfunction. However, the underlying mechanistic basis of the disease remains poorly understood. Herein, we review the current understanding, diagnosis and treatment of ME/CFS and summarize past clinical studies aimed at identifying effective therapies. We describe the current status of mechanistic studies, including the identification of multiple targets for potential pharmacological intervention, and ongoing efforts towards the discovery of new medicines for ME/CFS treatment.


Fourth and sixth nerve palsies due to Herpes Simplex 1 infection.
Ocular motor cranial nerve palsies of viral etiology are uncommon and, when accompanied by skin lesions, zoster ophthalmicus is the most frequent diagnosis. We describe the case of a 68-year-old woman who developed fourth and sixth nerve palsies 3 days after appearance of a painful vesicular skin rash on the left side of her forehead. Neuroimaging was normal but polymerase chain reaction (PCR) testing of the cerebrospinal fluid was positive for Herpes Simplex 1 and negative for Varicella Zoster. The patient was treated with intravenous acyclovir, and the cranial nerve palsies resolved over 7 weeks. Although the similarity of the cutaneous vesicular eruption in our patient to that seen with zoster might have led to an incorrect diagnosis, acyclovir seems to be safe and effective for both viral etiologies.


Dietary Lactobacillus plantarum LS/07 and inulin in the management of chronic disease risk factors.
The aim of this study was to investigate the possibilities of modification of chronic disease risk factors with probiotic strain Lactobacillus plantarum LS/07 and prebiotic inulin in rats with western high fat diet. The Sprague-Dawley rats were divided into four groups: control group (CG group), group with high fat diet (HFD group), group receiving high fat diet in combination with Lactobacillus plantarum LS/07 (HFD+PRO group), and group receiving high fat diet in combination with oligofructose enriched inulin (HFD+PRE group). The activity of β-glucuronidase, lipid parameters, bile acids, oxLDL, short chain fatty acids, and counts of coliforms and lactobacilli were determined. High fat diet as a key risk factor of chronic diseases had adverse effect on expression of metabolic and biochemical parameters. Dietary intake of Lactobacillus plantarum LS/07 (HFD+PRO group) and inulin (HFD+PRE group) suppressed weight gain of rats. In HFD+PRO group, the level of total cholesterol (P<0.001), LDL-CH (P<0.05), oxLDL (P<0.001), total bile acids (P<0.001) were statistically significantly decreased, while the production of short chain fatty acids was enhanced. Changes in the selected parameters exhibited a similar tendency also in the HFD+PRE group. Activity of β-glucuronidase was statistically significantly decreased (P<0.001) in the HFD+PRE group. Lactobacillus plantarum LS/07 and inulin caused a statistically significant increase in the count of lactobacilli (P<0.001) and a decrease in the number of coliforms (P<0.001). These results indicate Lactobacillus plantarum LS/07 and inulin could be used in diet for human and animals as an important nutritional supplement or in medicinal products.


Occasional-operator percutaneous brachial coronary angiography: first, do no arm.
The percutaneous brachial approach to coronary angiography is perceived, rightly or wrongly, to be the easiest of the arm approaches. Predominantly femoral operators may therefore be encouraged to use the percutaneous brachial approach as an occasional procedure. We decided to investigate prospectively whether this was a reasonable strategy by examining outcome in patients who underwent percutaneous brachial cardiac catheterization by occasional brachial operators. Between October 1997 and 2000, 55 patients underwent percutaneous brachial coronary angiography (0.6% of coronary angiographies), aged 66 +/- 10 years, of whom 40 (73%) were male. Chief indications for a brachial approach were peripheral vascular disease in 35 (64%), failed femoral approach in 10 (18%), and orthopnoea in 5 (9%). The procedure was completed successfully in 46 patients (84%). Reasons for failure were failure of access (two), brachial artery spasm (one), inability to negotiate brachial/subclavian tortuosity (two), dissection of the brachial artery (two), and inability to intubate a vein graft (two). Six patients required catheterization from an alternative site (brachial arteriotomy in two, percutaneous transradial in two, femoral in two), with success in all. There were complications of varying severity in 20 patients (36%). Major complications were false aneurysm requiring surgical repair (one), large brachial hematoma requiring surgical exploration and arterial repair (one), and hematoma with clinical median nerve dysfunction for one month. Minor complications included need for repeat coronary angiography via alternative approach (six), weakness of radial pulse < 24 hr (two), brachial artery dissection without clinical sequelae (two), brachial artery spasm terminating procedure (one), and wound oozing (three). Percutaneous brachial coronary angiography is a hazardous procedure when undertaken by occasional brachial operators. Complications are unacceptably frequent. As with all practical procedures, complication rates are likely to be inversely proportional to operator volumes. Patients requiring an arm approach should be referred to operators with high-volume brachial or radial experience.


Allele-specific methylation in the human genome: implications for genetic studies of complex disease.
Across the genome, outside of a small number of known imprinted genes and regions subject to X-inactivation in females, DNA methylation at CpG dinucleotides is often assumed to be complementary across both alleles in a diploid cell. However, recent findings suggest the reality is more complex, with the discovery that allele-specific methylation (ASM) is a common feature across the genome. A key observation is that the majority of ASM is associated with genetic variation in cis, although a noticeable proportion is also non-cis in nature and mediated, for example, by parental origin. ASM appears to be both quantitative, characterized by subtle skewing of DNA methylation between alleles, and heterogeneous, varying across tissues and between individuals. These findings have important implications for complex disease genetics; whilst cis-mediated ASM provides a functional consequence for non-coding genetic variation, heterogeneous and quantitative ASM complicates the identification of disease-associated loci. We propose that non-cis ASM could contribute toward the 'missing heritability' of complex diseases, rendering certain loci hemizygous and masking the direct association between genotype and phenotype. We suggest that the interpretation of results from genomewide association studies can be improved by the incorporation of epi-allelic information, and that in order to fully understand the extent and consequence of ASM in the human genome, a comprehensive sequencing-based analysis of allelic methylation patterns across tissues and individuals is required.


Interaction of tapasin related protein with cell surface MHC class 1 heavy chain molecules.
Tapasin related (TR) protein shares similarity (27%) with tapasin and is present in endoplasmic reticulam (ER) and on the cell surface of Hela cells. In the present article, TR protein was found localized in ER, but not in the lysosomes or late endosomes as studied by confocal colocalization. TR protein was associated with cell surface MHC class 1 HLA A2 heavy chain (HC) molecules and might be involved in chaperoning of cell surface HC MHC class 1 molecule. The results indicated that MHC class 1 cell surface molecules involved in antigen presentation of exogenous antigens, interact with cell surface chaperons.


Derived trail making test indices in a sample of hallucinogen abusers: demographic effects.
Derived indices on the Trail Making test (TMT), a test often used for screening for cognitive impairment, were examined in a sample of hallucinogen abusers in drug abuse treatment programs. A mixed race sample (N = 128) was drawn from electronic files of data from the Drug Abuse Treatment Outcome Study (DATOS). The DATOS was a naturalistic, prospective cohort study that collected data from 1991 to 1993 in 96 programs in 11 cities in the United States. Data were analyzed to determine the effects of demographic variables on derived indices created by adding, subtracting, multiplying, and dividing Parts A and B of the TMT in this large treatment sample of hallucinogen abusers. The variables of sex and age were not statistically significant for derived indices of the TMT. The variable of ethnicity was significant for the all derived indices except the ratio score (divide Part B by Part A) and the variable of education was significant for the interaction score (multiply Part A by Part B and divide by 100).


Vertebral bone metastasis in breast cancer: a case report.
We report here a case of a 66-year-old woman with a very aggressive form of breast carcinoma, having both liver and bone dissemination points. The patient was admitted for a rapid onset disk-herniation-like syndrome, but which on further investigation proved to be in fact a metastatic case of breast cancer. We found evidence of disseminations at least in the lumbar vertebral bodies and the liver. Pathological analysis of the available vertebral metastasis revealed a HER2+ molecular pattern, accordingly to the newly evolving molecular typing of breast cancers. Despite a rapid treatment instauration, the patient reacted poorly to taxanes and octeoclast inhibitors, and died after less than 11 months from admitting to the hospital. This is a rare case of an aggressive breast carcinoma identified initially after the vertebral metastases themselves that induced a non-specific symptomatology.


The Pseudomonas aeruginosa fumc and soda genes belong to an iron-responsive operon.
Pseudomonas aeruginosa contains two superoxide dismutases (SOD), a Mn-containing SOD (Mn-SOD) and a Fe-SOD, which are encoded by sodA and sodB, respectively. We have cloned and sequenced a DNA fragment from P. aeruginosa, strain CHA, which contains the sodA gene and three other open reading frames (ORF). We report here that one of the ORFs upstream from sodA is fumC, which encodes the O2.- resistant isoform of fumarase (or fumarate hydratase). It is shown that fumC and sodA belong to the same operon. By primer extension experiments, the transcription initiation site has been located at -413 from the ATG codon of the fumC gene. The fumC-sodA operon was found to be negatively regulated in presence of iron and the E. coli FUR protein was shown to bind to the 19-bp FUR consensus sequence present at the transcription start site of the operon.


[Effect of L-arg and LNNA on contractile-relaxant response and cGMP level of thoracic aorta with endothelial injury in rat].
In this study, we have observed the effect of L-arginine(L-arg) and omega N-nitro-L-arginine (LNNA) on the contractile-relaxation response and the cGMP level in arterial strip using the model of rat thoracic aorta with endothelial injury and neointimal formation. Organ chamber experiment and radioimmunoassay showed that, the 3rd day after endothelial injury of the rat thoracic aorta, their endothelium-dependent relaxtion response caused by L-arg, as well as endothelium dependent contractile response caused by LNNA were impaired seriously, basic cGMP reduced obviously, and the change of cGMP caused by L-Arg and LNNA was impaired markedly. On the 10th day after injury a pronounced recovery was noticed, and 21st day, the situation was further improved, but could not restore completely. The results indicate that the production of EDRF in the rat thoracic aorta after endothelial injury may be impaired seriously, and could not recover completely for a longer time.


[A hygienic analysis of the irradiation doses of those cleaning up the aftermath of the accident at the Chernobyl Atomic Electric Power Station (based on data from the All-Army Registry)].
In the result of the analysis of irradiation doses of 36,895 servicemen who have participated in liquidation of the Chernobyl APC disaster consequences it was found out that the average radiation dose was 12.1 cSv in 1986, 8.4 cSv in 1987, and in 1988-90 it didn't exceed 5 cSv. The irradiation received by these servicemen has depended on the time of their arrival to the zone of the disaster, the maximum permissible doses of radiation established at that period, the character of their activities and the place of their work, utilization of protection means. A conclusion was made that irradiation dose itself could be considered only as a general guide reference, because it didn't take into consideration internal irradiation and beta-irradiation of skin. That's why it is necessary to continue the further monitoring over the health status of liquidators independently of the doses of irradiation which were fixed in their histories.


The hybrid process TiO(2)/PAC: performance of membrane filtration.
In investigations concerning the photocatalytic degradation by TiO(2) usually filter discs with a pore size of 0.22 mum and 0.45 mum are used for the removal of photocatalyst particles in aqueous suspensions. In this study the effective rejection of suspended particles by microfiltration in different types of membrane modules and with different membrane materials was investigated. Furthermore, Powdered Activated Carbon (PAC), which can be used to gain an increase in photocatalytic degradation rates, was investigated concerning its influence on the membrane performance. It is shown that by membrane filtration with a pore size above 0.1 mum, irrespective of the experimental conditions, no complete removal can be achieved. However, UV irradiation was found to improve the removal efficiency for all types of tested membrane materials. The addition of PAC also led to a higher performance of membrane filtration with regard to particle rejection. In long-term experiments with a hollow fibre membrane module in the presence of PAC a five-fold decrease of TiO(2) particles in the permeate could be proven. Besides, it was shown that added PAC can shield the membrane regarding the abrasivity of TiO(2), which could otherwise lead to the destruction of the membrane. Therewith PAC exhibits another crucial advantage besides its synergetic effect in photodegradation.


Sitagliptin down-regulates retinol-binding protein 4 and reduces insulin resistance in gestational diabetes mellitus: a randomized and double-blind trial.
Gestational diabetes mellitus (GDM) is a condition that affects increasing number of pregnant women worldwide. Sitagliptin was reported to alleviate symptoms of type 2 diabetes mellitus by reducing serum levels of retinol-binding protein 4 (RBP-4). We investigated the effectiveness of sitagliptin on insulin sensitivity parameters in GDM patients. Pregnant GDM women in the 2nd trimester were recruited for this study. Participants were then assigned randomly to sitagliptin treatment group or placebo treatment group, and administered sitagliptin or placebo daily for 16 weeks. Glucose and insulin profiles, as well as serum RBP-4 level, were measured at both baseline and end of the study. After 16 weeks of treatment, participants in the STL group exhibited significantly improved levels of fasting plasma glucose and serum insulin, homeostasis model of assessment of β cell function (HOMA-β) and insulin resistance (HOMA-IR), compared with those in the placebo group. Serum levels of RBP-4 were also markedly decreased in the sitagliptin treatment group, and more importantly it was positively correlated with improved insulin resistance parameters. Our study supports a potentially promising role of sitagliptin in improving insulin resistance by decreasing RBP-4 in GDM-affected women.


An update on drug-drug interactions between antiretroviral therapies and drugs of abuse in HIV systems.
While considerable progress has been made in the fight against HIV/AIDS, to date there has not been a cure, and millions of people around the world are currently living with HIV/AIDS. People living with HIV/AIDS have substance abuse disorders at higher rates than non-infected individuals, which puts them at an increased risk of drug-drug interactions. Potential drug-drug interactions are reviewed for a variety of potential drugs of abuse, both licit and illicit. These drugs include alcohol, cigarettes or other nicotine delivery systems, methamphetamine, cocaine, opioids, and marijuana. Potential interactions include decreased adherence, modulation of drug transporters, or modulation of metabolic enzymes. We also review the relative incidence of the use of these drugs of abuse in People living with HIV/AIDS. Despite considerable improvements in outcomes, disparities in outcomes between PLWHA who use drugs of abuse, vs those who do not still exist. It is of critical necessity to improve outcomes in these patients and to work with them to stop abusing drugs of abuse.


Ribozyme cleavage reveals connections between mRNA release from the site of transcription and pre-mRNA processing.
We report a functional connection between splicing and transcript release from the DNA. A Pol II CTD mutant inhibited not only splicing but also RNA release from the site of transcription. A ribozyme situated downstream of the gene restored accurate splicing inhibited by the CTD mutant or a mutant poly(A) site, suggesting that cleavage liberates RNA from a niche that is inaccessible to splicing factors. Although ribozyme cleavage enhanced splicing, 3' end processing was impaired, indicating that an intact RNA chain linking the poly(A) site to Pol II is required for optimal processing. Surprisingly, poly(A)(-) beta-globin mRNA with a ribozyme-generated 3' end was exported to the cytoplasm. Ribozyme cleavage can therefore substitute for normal 3' end processing in stimulating splicing and mRNA export. We propose that mRNA biogenesis is coordinated by preventing splicing near the 3' end until the transcript is released by poly(A) site cleavage.


Genetically engineered mouse models of astrocytoma: GEMs in the rough?
Astrocytomas are the most common form of brain cancer and are essentially incurable due to their diffusely infiltrative nature. Mouse models of astrocytoma provide a useful system for understanding tumorigenesis of astrocytomas and for designing and testing new therapies. Although molecular genetic alterations have been characterized in human astrocytomas, many of the mice engineered with these mutations do not develop astrocytomas. Recently, successful modeling of astrocytoma in the mouse has suggested that the combination of molecular alterations, the cell type in which the alterations take place, and the strain background all play a role in generating a model of astrocytoma.


Influence of the interlayer on coupling of surface plasmons in a sandwiched structure with periodic array of nanoapertures.
In this work, we investigate the optical properties of a multilayer structure, where a SiO2 film is sandwiched by silver films with periodic array of sub-wavelength apertures. Due to the coupling of surface plasmons (SPs) between different layers, electric and magnetic resonances have been observed. By varying the thickness of the interlayer SiO2, we can modify relative phase of the SPs resonance and control the shifts of transmission peaks. Experimentally the multilayers are fabricated by magnetron sputtering and the array of apertures is milled by focused-ion-beam facility. The measured optical transmission spectra reasonably agree with our numerical calculation, which bases on three-dimensional finite-difference time-domain method. To understand the shifts of the peaks, we present a phenomenological explanation, considering the transmission peaks as energy levels, and the coupling of localized surface plasmons as perturbation. These results may have potential applications in designing plasmonic devices and tuning electromagnetic wave in nanophotonics.


Effect of 2-mercaptopropionylglycine on lipid peroxidation and drug oxidation in rat liver microsomes.
2-Mercaptopropionylglycine, a synthetic thiol, significantly stimulated NADPH-dependent lipid peroxidation by rat liver microsomes, while the thiol inhibited the microsomal aminopyrine N-demethylase activity with an increase in lipid peroxidation. But, a strong inhibition of lipid peroxidation by EDTA could not abolish the inhibition of the N-demethylase activity by the thiol. Besides, the thiol markedly increased not only the Km value for aminopyrine N-demethylase but also the apparent Ks value for aminopyrine binding to the microsomal oxidized cytochrome P-450 by interacting with the cytochrome P-450.


Hydraulic constraints in the functional scaling of trees.
I conducted a literature survey to assess the available information on relationships between size--expressed in terms of diameter and dry biomass--and hydraulic efficiency of woody structures at different scales, from stem segments to whole trees. Three data sets were constructed: the first described the relationship between segment diameter and hydraulic conductivity (k(h); kg m s(-1) MPa(-1)) in four species; the second, for the same four species, described the intraspecific trajectories of change in total hydraulic conductance (G; kg s(-1) MPa(-1)) during ontogeny, i.e., from saplings to mature trees, thereby providing a comparison between allometric scaling laws at the scales of segments and whole trees; the third comprised pooled means for nine species that described the interspecific trajectory of change in G with tree size. The scaling coefficients obtained were compared with predictions made with an architectural fractal-like model incorporating tissue-specific hydraulic architecture parameters (West et al. 1999). When data on segment k(h) were examined, the fractal-like model closely predicted the scaling of k(h) with segment diameter in four species. However, the model failed to predict accurately in all species the intraspecific scaling at the branch and whole-tree levels, and consistently overestimated the scaling coefficients. The results suggest that ontogenetic changes in tree size during the life cycle of one tree may result in tradeoffs between optimal hydraulic supply to the existing leaf area and maintenance costs of the supporting xylem tissue. The model of West et al. (1999) may be useful for understanding broad interspecific patterns, but not for understanding more subtle ontogenetic changes.


Central Nervous System Effects of Iso-6-spectaline Isolated from Senna Spectabilis var. Excelsa (Schrad) in Mice.
The central nervous system (CNS) depressant and anticonvulsant activities of iso-6-spectaline (SPEC) were investigated in animal models. The SPEC from Senna spectabilis var. excelsa (Schrad) (0.1, 0.5 and 1.0 mg/ kg) injected by oral route (p.o.) in mice caused a significant decrease in the motor activity up to 30 days after the administration and in the dose of 1.0 mg/kg significantly reduced the remaining time on the Rota-rod apparatus. Additionally, SPEC (0.1, 0.5 and 1.0 mg/kg, p.o.) was also capable of promoting increase of latency for development of convulsions induced by pentylenetetrazole. This SPEC was also capable of promoting an increase of latency for development of convulsions induced by picrotoxin at highest dose. In the same way, the anticonvulsant effect of SPEC was affected by pretreatment with flumazenil, a selective antagonist of the benzodiazepine site of the GABA(A) receptor. These results suggest possible CNS depressant and anticonvulsant activities in mice that needs further investigation.


General nurses' experiences of end-of-life care in the acute hospital setting: a literature review.
Approximately 90% of the UK population spend some time in hospital in their final year of life, and more than half of the population die in hospital. This review aims to explore the experiences of general nurses when providing end-of-life care to patients in the acute hospital setting. Nine studies were identified through a literature search, and each was then analysed and evaluated until themes emerged. Six themes were drawn from the literature: lack of education and knowledge, lack of time with patients, barriers arising in the culture of the health-care setting, communication barriers, symptom management, and nurses' personal issues. The themes cause concern about the quality of end-of-life care being provided in the acute care setting. The literature appears to be consistent in the view that terminally ill patients are best cared for in specialised care settings, such as palliative care units and hospices. However, increasing demands on health services will result in greater numbers of dying patients being admitted to the acute hospital setting. It is therefore paramount that general nurses' educational needs are met to ensure they develop clinical competence to provide high-quality holistic end-of-life care.


Fibrolipomatous hamartoma of the median nerve: A cause of acute bilateral carpal tunnel syndrome in a three-year-old child: A case report and comprehensive literature review.
A three-year-old boy was investigated for inexplicable incessant crying. On examination, his left wrist was mildly swollen (three to four months) and sensitive. Exploration and carpal tunnel decompression of the left wrist with incisional biopsy was performed for the presence of a fusiform swelling intimately associated with the median nerve. Histopathology revealed the presence of enlarged nerve bundles admixed with mature fat cells and diffuse fibroblastic proliferation. Three months later, he underwent urgent contralateral carpal tunnel decompression for a similar presentation. The final diagnosis was bilateral fibrolipomatous hamartoma (FLH) of the median nerves causing acute bilateral compression neuropathy. FLH of the median nerve is an extremely unusual cause of acute bilateral carpal tunnel syndrome in a young child presenting with 'incessant crying'. A comprehensive review of FLH including epidemiology, etiology, clinical presentation, differential diagnosis, imaging, pathology, treatment and prognosis is discussed.


Histone Deacetylation Controls Xylem Vessel Cell Differentiation via Transcriptional Regulation of a Transcription Repressor Complex OFP1/4-MYB75-KNAT7-BLH6.
Xylem vessels are indispensable tissues in vascular plants that transport water and minerals. The differentiation of xylem vessel cells is characterized by secondary cell wall deposition and programmed cell death. These processes are initiated by a specific set of transcription factors, called VASCULAR-RELATED NAC-DOMAIN (VND) family proteins, through the direct and/or indirectly induction of genes required for secondary cell wall deposition and programmed cell death. In this study, we explored novel regulatory factors for xylem vessel cell differentiation in Arabidopsis thaliana. We tested the effects of cellular stress inducers on VND7-induced differentiation of xylem vessel cells with the VND7-VP16-GR system, in which VND7 activity is post-translationally induced by dexamethasone application. We established that the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sirtinol inhibited VND7-induced xylem vessel cell differentiation. The inhibitory effects of TSA and sirtinol treatment were detected only when they were added at the same time as the dexamethasone application, suggesting that TSA and sirtinol mainly influence the early stages of xylem vessel cell differentiation. Expression analysis revealed that these HDAC inhibitors downregulated VND7-downstream genes, including both direct and indirect targets of transcriptional activation. Notably, the HDAC inhibitors upregulated the transcript levels of negative regulators of xylem vessel cells, OVATE FAMILY PROTEIN1 (OFP1), OFP4, and MYB75, which are known to form a protein complex with BEL1-LIKE HOMEODOMAIN6 (BLH6) to repress gene transcription. The KDB system, another in vitro induction system of ectopic xylem vessel cells, demonstrated that TSA and sirtinol also inhibited ectopic formation of xylem vessel cells, and this inhibition was partially suppressed in knat7-1, bhl6-1, knat7-1 bhl6-1, and quintuple ofp1 ofp2 ofp3 ofp4 ofp5 mutants. Thus, the negative effects of HDAC inhibitors on xylem vessel cell differentiation are mediated, at least partly, by the abnormal upregulation of the transcriptional repressor complex OFP1/4-MYB75-KNAT7-BLH6. Collectively, our findings suggest that active regulation of histone deacetylation by HDACs is involved in xylem vessel cell differentiation via the OFP1/4-MYB75-KNAT7-BLH6 complex.


[Chromosomal mosaicism of extraembryonic cell membrane, detected during prenatal diagnosis].
Data on detection of chromosomal mosaicism in amnionic cells and chorionic villi obtained by prenatal cytogenic diagnosis are presented. The frequency of chromosomal mosaicism in preparations of amniotic fluid cell culture was 2.6% (6 out of 226), and that in "direct" villus preparations was 1.6% (13 out of 774). The necessity perform an additional analysis of other fetal cells or neonatal lymphocytes to specify the diagnosis was shown. The analysis of the outcome of pregnancies during which chromosomal mosaicism in the extraembryonic cells was detected indicates that these women from a high-risk group of at, both genetically and obstetrically: in only 8 out of 19 cases did pregnancies end in normal deliveries at term; in three cases, spontaneous abortions occurred at 16-31 weeks of gestation; in three cases, the pregnancies were terminated due to fetal chromosomal aberrations in nonmosaic form; the outcome of pregnancy in five cases was preterm delivery of an underweight newborn.


Core Competencies in Integrative Pain Care for Entry-Level Primary Care Physicians.
The objective was to develop a set of core competencies for graduating primary care physicians in integrative pain care (IPC), using the Accreditation Council for Graduate Medical Education (ACGME) domains. These competencies build on previous work in competencies for integrative medicine, interprofessional education, and pain medicine and are proposed for inclusion in residency training. A task force was formed to include representation from various professionals who are involved in education, research, and the practice of IPC and who represent broad areas of expertise. The task force convened during a 1.5-day face-to-face meeting, followed by a series of surveys and other vetting processes involving diverse interprofessional groups, which led to the consensus of a final set of competencies. The proposed competencies focus on interprofessional knowledge, skills, and attitudes (KSAs) and are in line with recommendations by the Institute of Medicine, military medicine, and professional pain societies advocating the need for coordination and integration of services for effective pain care with reduced risk and cost and improved outcomes. These ACGME domain compatible competencies for physicians reflect the contributions of several disciplines that will need to be included in evolving interprofessional settings and underscore the need for collaborative care. These core competencies can guide the incorporation of KSAs within curricula. The learning experiences should enable medical educators and graduating primary care physicians to focus more on integrative approaches, interprofessional team-based, patient-centered care that use evidence-based, traditional and complementary disciplines and therapeutics to provide safe and effective treatments for people in pain.


A ligand for human CD48 on epithelial cells.
CD48 is a member of the Ig superfamily with a high degree of sequence homology to CD58 (LFA-3). In rodents, CD48 is the ligand for CD2 whereas in humans, CD58 is the ligand for CD2. Despite intensive efforts, no ligand for human CD48 has been convincingly demonstrated. We now show that a ligand for human CD48 is present on epithelial cells. The ligand was detected based on the ability of epithelial cells to bind both a decameric, soluble CD48 IgM fusion protein and monomeric CD48 immobilized on plastic dishes. mAbs raised to the ligand completely block binding of CD48 to all epithelial cells tested. We further show that the cell surface proteoglycan CD44 plays an auxiliary role in the binding of epithelial cells to CD48 and that this interaction involves the glycosaminoglycan binding site of CD44. No interaction of human CD48 with CD2 was detected. This is the first clear demonstration that human CD48 can function as an adhesion molecule and suggests a role for CD48 in lymphocyte epithelial cell interactions.


Family financial socialization during emerging adulthood: Insights from a cross-lagged panel model.
The present study tested the Gudmunson and Danes (2011) family financial socialization model (FFSM) using three waves of longitudinal data gathered from a college cohort of emerging adults in the United States. Specifically, we aimed to test the validity of this model in emerging adulthood (Aim 1), to verify whether the effect of the parent's socialization on a child's end financial outcome is mediated by intermediary financial outcomes (Aim 2), and to verify whether the effects found when testing the FFSM are stable across time points (Aim 3). Our findings indicate that of eight paths in the model between family socialization processes and financial socialization outcomes, seven paths were significant, thereby lending support for the validity of FFSM in emerging adulthood (Aim 1). Second, we found no mediation effects of parental financial socialization on emerging adult financial behavior and well-being via the internalization of parents' beliefs, values, and practices (Aim 2). We offer plausible explanations for this result. Last, we verified that the financial socialization processes and their effects are generally invariant across the beginning, the middle, and the end of the emerging adulthood (Aim 3). We interpret our findings in the context of the extant literature on emerging adults' transition to adult independence and provide insights for practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Transverse cervical artery fasciocutaneous free flap for head and neck reconstruction: initial anatomic and dye studies.
The bilateral transverse cervical arteries of 16 fresh cadavers were exposed by an infraclavicular midline approach. Each artery was cannulated, and methylene blue dye was infused to delineate the skin territory subserved by the vessel. The two major infusion skin patterns obtained allowed fashioning of a thin fasciocutaneous flap incorporating supraclavicular skin, which was based on the transverse cervical artery; or a larger flap additionally incorporating upper back skin and varying amounts of trapezius muscle, when the artery had a dorsal scapular artery branch. Depending on the skin pattern, either scapula or clavicle could be transferred with the other soft tissues. The skin territory of the transverse cervical artery is caused to vary by the presence or absence of its dorsal scapular artery branch. The supraclavicular portion of the flap is recommended for repair of facial and nasal lesions because of its close match in color and texture to facial skin. Oral lesions can also be reconstructed with this flap because of its pliability. The free flap based on the transverse cervical artery pedicle appears to be a useful addition to the armamentarium of flaps for head and neck reconstruction. Clinical use of the flap is ongoing and will be subsequently reported.


Supramolecular self-organization of "Janus-like" diblock codendrimers: synthesis, thermal behavior, and phase structure modeling.
We report on the design and synthesis of three series of segmented amphiphilic block codendrimers, and on their self-organizing behavior in liquid-crystalline mesophases. Connecting two prefunctionalized monodendrons, each differing in their chemical constitution and generation number, yielded these diblock supermolecules. One wedge of the codendrimer was made hydrophobic, and is based on a branched poly(benzyl ether) monodendron functionalized at the periphery by lipophilic aliphatic fragments (also known as Percec dendrons). The other segment was made hydrophilic by the grafting of hydroxyl-containing moieties onto the focal functions of the former dendrons. Both types of dendrons were prepared independently by convergent methods and then joined in the ultimate stage of the synthetic procedure by cross-coupling reactions. In this way, the proportion of the dendritic blocks was varied independently to allow control of the hydrophilic/hydrophobic balance (HHB), the hydrogen-bonding ability, and consequently the capacity to tune the mesomorphic properties of the resulting "superamphiphiles" was anticipated. Essentially all the dendritic compounds display a thermotropic mesomorphism directly at or near room temperature as determined by using X-ray diffraction, polarized optical microscopy, and differential scanning calorimetry. The nature and the supramolecular organization of the mesophases, namely columnar and cubic phases, are correlated to the size of the respective block monodendrons and the chemical structures of the dendromesogens. The molecular organization within the cubic phases can be geometrically described and well understood by the space-filling polyhedron model.


Liver resection and transplantation in hepatocellular carcinoma.
Liver resection is the most available, efficient treatment for patients with hepatocellular carcinoma. Better liver function assessment, increased understanding of segmental liver anatomy using more accurate imaging studies, and surgical technical progress are the most important factors that have led to reduced mortality, with an expected 5 year survival of 70%. Impairment of liver function and the risk of tumor recurrence lead to consideration of liver transplantation (LT) as the ideal treatment for removal of the existing tumor and the preneoplastic underlying liver tissue. However, LT, which is not available in many countries, is restricted to patients with minimum risk of tumor recurrence under immunosuppression. Limited availability of grafts as well as the risk and the cost of the LT procedure has led to considerable interest in combined treatment involving resection and LT. An increasing amount of evidence has shown that initial liver resection in transplantable patients with a single limited tumor and good liver function is a valid indication. Histological analysis of specimens allows identification of the subgroup of patients who could benefit from follow-up with LT in case of recurrence.


Calcium antagonist (PY 108-068) treatment may further decrease flow in ischemic areas in acute stroke.
The effect of the possible influence of a new calcium antagonist, PY 108-068, on regional CBF was studied in patients suffering acute ischemic stroke. The dosage was 1.5 + 2.5 mg intravenously in six patients (series 1) and 2.5 + 5.0 mg intravenously in five other patients (series 2). CBF was measured before and after treatment by xenon-133 inhalation and single-photon emission computed tomography (Tomomatic 64). In the first series, no changes in hemispheric CBF, MABP, or clinical symptoms were noted after treatment, but one patient showed an increase of CBF in part of the periinfarct area. In the second series, slight increases in mean hemispheric flow values were seen, but in three of the five patients CBF decreased even further in the ischemic area. MABP decreased by 13%, and the clinical symptoms were unchanged.


Responses of a looming-sensitive neuron to compound and paired object approaches.
The lobula giant movement detector (LGMD) and its target neuron, the descending contralateral movement detector (DCMD), constitute a motion-sensitive pathway in the locust visual system that responds preferentially to objects approaching on a collision course. LGMD receptive field properties, anisotropic distribution of local retinotopic inputs across the visual field, and localized habituation to repeated stimuli suggest that this pathway should be sensitive to approaches of individual objects within a complex visual scene. We presented locusts with compound looming objects while recording from the DCMD to test the effects of nonuniform edge expansion on looming responses. We also presented paired objects approaching from different regions of the visual field at nonoverlapping, closely timed and simultaneous approach intervals to study DCMD responses to multiple looming stimuli. We found that looming compound objects evoked characteristic responses in the DCMD and that the time of peak firing was consistent with predicted values based on a weighted ratio of the half size of each distinct object edge and the absolute approach velocity. We also found that the azimuthal position and interval of paired approaches affected DCMD firing properties and that DCMDs responded to individual objects approaching within 106 ms of each other. Moreover, comparisons between individual and paired approaches revealed that overlapping approaches are processed in a strongly sublinear manner. These findings are consistent with biophysical mechanisms that produce nonlinear integration of excitatory and feed-forward inhibitory inputs onto the LGMD that have been shown to underlie responses to looming stimuli.


Practice redesign to improve care for falls and urinary incontinence: primary care intervention for older patients.
In primary care, medical care for age-associated conditions, such as falls and urinary incontinence (UI), is inadequate. In collaboration with the American College of Physicians, we augmented the Assessing Care of Vulnerable Elders practice redesign intervention to improve falls and UI care. We performed a controlled trial in 5 nonrandomly selected primary care intervention (26 physicians across sites) and control (18 physicians) practices from diverse communities. Patients 75 years and older who screened positive for falls or fear of falling and UI were included in the study. We conducted a multicomponent intervention between October 30, 2006, and December 31, 2007, that included efficient collection of data, medical record prompts, patient education materials, and physician decision support. Main outcome measures were quality of care for falls and UI comparing intervention and control sites. Of 6051 patients screened, 2847 (47.1%) screened positive for falls or UI (46.1% in the intervention group and 48.8% in the control group). Across the 5 practices, 1211 patient medical records were evaluated after stratified random selection. Intervention patients received 60.0% of recommended care for falls vs 37.6% provided by control health care professionals (P < .001). Similarly, intervention health care professionals provided more recommended care for UI (47.2% vs 27.8%, P < .001). Intervention health care professionals more often performed a falls history, orthostatic blood pressure measurement, gait and balance examination, and UI history and tried UI behavioral treatments first. Knowledge about falls and UI increased more among intervention than control group health care professionals. Practice redesign can improve the care that community-based primary care physicians provide for older patients with falls and UI. Outcomes of such care improvements require further evaluation.


The solute-solvent system: solvent constraints on the conformational dynamics of acetylcholine.
The objective of this study was to determine if and how a solvent influences internal motions in a solute molecule. Acetylcholine was chosen as the object of study given its interesting molecular structure and major biological significance. Molecular dynamics simulations were carried out in the vacuum (10 ns), water (5 ns), methanol (5 ns), and octanol (1.5 ns). Seven clusters of conformers were identified, namely, +g+g, -g-g, +gt, -gt, t+g, t-g, and tt, where the gauche and trans labels refer to the dihedral angles tau(2) and tau(3), respectively. As expected, the relative proportion of these conformational clusters was highly solvent-dependent and corresponded to a progressive loss of conformational freedom with increasing molecular weight of the solvent. More importantly, the conformational clusters were used to calculate instantaneous and median angular velocity (omega and omega(M), respectively) and instantaneous and median angular acceleration (alpha and alpha(M), respectively). Angular velocity and angular acceleration were both found to decrease markedly with increasing molecular weight of the solvent, i.e., vacuum (epsilon = 1) > water > methanol > octanol. The decrease from the vacuum to octanol was approximately 40% for tau(2) and approximately 60% for tau(3). Such solvent-dependent constraints on a solute's internal motions may be biologically and pharmacologically relevant.


The diagnosis and treatment of pyogenic liver abscesses.
Pyogenic liver abscesses in 106 adult patients at The New York Hospital were reviewed to define optimum treatment. Mortality in the surgically treated patients was 26% (17/65), while those treated nonsurgically had a fatality rate of 95% (39/41). Multiple abscesses treated surgically had a surprisingly low mortality of 29% (5/17). Modern noninvasive tests are highly sensitive in diagnosing liver lesions greater than 2 cm. Difficulty remains in identifying small hepatic abscesses and differentiating large abscesses from tumor. Most liver abscesses have an identifiable source outside the liver. The most common source (31%) was cholangitis secondary to extrahepatic biliary obstruction. Multiple abscesses, mixed organisms, hyperbilirubinemia, and abscess complications are all associated with a significantly increased mortality. However, the lethality of the primary disease process was the most important factor determining survival. Most patients who have the underlying pathogenesis of the abscess controlled will survive surgical treatment. Transperitoneal surgical drainage and antibiotics remain the mainstay of treatment. Percutaneous drainage is recommended for high risk patients only.


A case of cutaneous Mycobacterium chelonae abscessus infection in a renal transplant patient.
Mycobacterium chelonae is an atypical "fast-growing Mycobacteria" that is a rare cause of human infection. There have been several reports of cutaneous infection among immunosuppressed patients, as well as in immunocompetent individuals following trauma. Most cases to date seem to have occurred among renal transplant recipients, raising the possibility that there is something inherent to the renal transplant patient that increases their susceptibility more than other immunocompromised patients. The differential diagnosis of subcutaneous nodules distributed in a sporotrichoid pattern is extensive, particularly in an immunocompromised host. Although several cases of cutaneous M. chelonae abscessus infection have been reported among both immunosuppressed and immunocompetent patients, the clinical presentation has varied, and few cases have reported the appearance of lesions in a sporotrichoid pattern. We present a case of a renal transplant patient with a reported history of trauma to the lower extremities, who presents with subcutaneous nodules distributed in a sporotrichoid pattern. The patient is found to have M. chelonae abscessus infection, fails several treatment regimens, and presents with a recurrence. The literature of M. chelonae infection is reviewed, and the various treatment options are discussed. An initial skin biopsy was stained with Hematoxylin and Eosin and revealed deep dermal abscesses with acid-fast bacilli in clusters. The culture became positive for Mycobacterium chelonae abscesses in four days and was found to be sensitive to multiple antibiotics. The patient underwent surgical excision of 14 nodules, which revealed findings consistent with the skin biopsy, and was subsequently treated with the appropriate antibiotics. Despite treatment with a full course of an organism-sensitive antibiotic regimen, the patient returned with persistent and recurrent nodules six weeks later. The patient was then treated as an inpatient with a seven-week course of intravenous antibiotics and was discharged home on a combined intravenous and oral regimen. Although M. chelonae abscessus is an extremely rare cause of infection among humans, there seems to be a predominance of cases reported among renal transplant patients. The explanation for this is not entirely clear; however, the organism must be considered as a cause of infection in any renal transplant recipient who presents with subcutaneous nodules. Eradication of the organism presents a tremendous challenge to the clinician, and, as presented here, even with appropriate antibiotics, there is a high rate of recurrence.


Short segment Barrett's esophagus: clinical and histological features, associated endoscopic findings, and association with gastric intestinal metaplasia.
To prospectively determine the clinical features, associated esophageal endoscopic lesions, associated gastric intestinal metaplasia, and prevalence of dysplasia and adenocarcinoma of short segment Barrett's. All patients undergoing upper endoscopy over a 5-month period were scrutinized for endoscopic features suggestive of short segment Barrett's, and, if present, multiple biopsies were obtained from the suspicious areas. Prevalence of gastric intestinal metaplasia was determined by obtaining biopsies from the antrum, body, and cardia. Two hundred thirty seven patients were examined. Short segment Barrett's was suspected in only 42 patients, and traditional Barrett's was noted in 45 patients. Short segment Barrett's was confirmed by biopsy in 48%. Clinical presentation of short segment Barrett's was that of typical or complicated gastroesophageal reflux disease in 53%. A hiatal hernia was the most common associated esophageal endoscopic finding; however, none of the endoscopic findings differed significantly from findings of patients who did not have short segment Barrett's. Diagnosis of short segment Barrett's required histological analysis. A significant difference was noted in the prevalence of intestinal metaplasia between the esophagus and stomach in patients with Barrett's. No dysplasia or adenocarcinoma was detected in patients with short segment Barrett's. Short segment Barrett's is a frequent finding in patients undergoing upper endoscopy. All patients with short tongues or patches of red mucosa lying less than 2 cm above the esophagogastric junction should be biopsied to exclude short segment Barrett's. Large scale endoscopic and histological surveillance studies along with long-term follow-up are required to clarify short segment Barrett's prevalence and cancer risk.


Characterization and functional study of five novel monoclonal antibodies against human OX40L highlight reverse signalling: enhancement of IgG production of B cells and promotion of maturation of DCs.
OX40 ligand (OX40L), a molecule originally identified as human gp34, is an important co-stimulatory molecule during immune response. In this study, we report on five functional mouse anti-human OX40L monoclonal antibodies named as 9H10, 4C12, 8D10, 4H4 and 1G1, characterized by means of flow cytometry, Western blot and competition assay. These monoclonal antibodies bound to distinct OX40L epitopes on activated B cells and dendritic cells (DCs) and two of them could suppress the proliferation of T lymphocytes co-stimulated by mature DCs. Furthermore, we demonstrated that our monoclonal antibodies, such as 9H10 and 4C12, could trigger OX40L reverse signal that enhanced IgG production of B cells and promoted maturation of DCs as evidenced by the upexpression of CD80, CD86, CD83 and CXCR4 and monoclonal antibody 9H10 could also promote anti-CD40 monoclonal-antibody-stimulated DCs in order to induce T cells to secrete more interleukin-2 and interferon-gamma, which suggested that OX40L signals could strengthen the effect of CD40 signals on promoting Th1 differentiation.


15 Years in surgical management of pulmonary hydatidosis.
Echinococcosis remains an endemic surgical problem in countries where sheep and cattle raising is carried out, particularly in many Mediterranean countries. This study aims to evaluate the management of different presentations of pulmonary hydatidosis and their outcome over 15 years. Retrospective study. Thoracic surgical department, Chest Diseases Hospital, Kuwait. Sixty patients operated upon for hydatid disease were evaluated pre- and post- operatively; 35 males, 25 females with a mean age of 28.4 years. Most patients were investigated by laboratory, serological and radiological studies. Different surgical techniques were used to remove the hydatid cyst from the lung. The most common presenting symptoms were cough (41 patients), and 12 patients were asymptomatic. Chest X-ray showed a rounded shadow in 42 patients; 19 cases were of vigorous size >10 cm. Thoracotomy was done in 57 patients; two chest wall cases were managed by minimal skin incision and enucleation, one hydatid cyst of the heart was approached through a median sternotomy. The mean hospital stay was 9 days. Postoperative complications occurred in 9 patients; prolonged air leak in 4 patients, pleural effusion in 3, pneumothorax, and wound infection in one patient each. One patient (65 years old) died on the 6th post-operative day most probably from pulmonary embolism. In a follow-up period of 2-15 years, 4 recurrences have been noted. Surgical excision of pulmonary hydatidosis with maximum preservation of the lung parenchyma is the main stay of treatment.


Current Impact of Cardiopulmonary Bypass in Coronary Artery Bypass Grafting in São Paulo State.
Previous results on the use of cardiopulmonary bypass (CPB) have generated difficulties in choosing the best treatment for each patient undergoing myocardial revascularization surgery (CABG) in the current context. Evaluate the current impact of CPB in CABG in São Paulo State. A total of 2905 patients who underwent CABG were consecutively analyzed in 11 São Paulo State centers belonging to the São Paulo Registry of Cardiovascular Surgery (REPLICCAR) I. Perioperative and follow-up data were included online by trained specialists in each hospital. Associations of the perioperative variables with the type of procedure and with the outcomes were analyzed. The study outcomes were morbidity and operative mortality. The expected mortality was calculated using EuroSCORE II (ESII). The values of p <5% were considered significant. There were no significant differences concerning the patients' age between the groups (p=0.081). 72.9% of the patients were males. Of the patients, 542 underwent surgery without CPB (18.7%). Of the preoperative characteristics, patients with previous myocardial infarction (p=0.005) and ventricular dysfunction (p=0.031) underwent surgery with CPB. However, emergency or New York Heart Association (NYHA) class IV patients underwent surgery without CPB (p<0.001). The ESII value was similar in both groups (p=0.427). In CABG without CPB, the radial graft was preferred (p<0.001), and in CABG with CPB the right mammary artery was the preferred one (p<0.001). In the postoperative period, CPB use was associated with reoperation for bleeding (p=0.012). Currently in the REPLICCAR, reoperation for bleeding was the only outcome associated with the use of CPB in CABG. (Arq Bras Cardiol. 2020; 115(4):595-601).


The myosin-bound form of protein phosphatase 1 (PP-1M) is the enzyme that dephosphorylates native myosin in skeletal and cardiac muscles.
The myosin-bound form of protein phosphatase 1 (PP-1M) and the glycogen-bound form (PP-1G) together account for virtually all the phosphatase activity in rabbit skeletal muscle extracts towards native myosin. PP-1M has a 3-fold higher activity towards native myosin than does PP-1G and accounts for at least 60% of the myosin phosphatase activity in rabbit skeletal muscle. PP-1M accounts for 90% of the myosin phosphatase activity in bovine cardiac muscle, where PP-1G is essentially absent. The high activity of PP-1M towards native myosin appears to arise from interaction of the catalytic subunit with the putative myosin-binding subunit, since chymotryptic digestion liberates a catalytic subunit having the same characteristics as that released by limited proteolysis of PP-1G. Protein phosphatase 2A in skeletal and cardiac muscles is very active towards the isolated myosin P-light chain, but ineffective in dephosphorylating native myosin. The results suggest that PP-1M is the enzyme that dephosphorylates myosin in skeletal and cardiac muscle.


N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury.
The placenta is susceptible to diverse insults during human pregnancy. The expression of the protein N-myc down-regulated gene 1 (NDRG1) is regulated during cell proliferation, differentiation, and in response to stress. Nevertheless, the function of this protein in humans remains unknown. We tested the hypothesis that NDRG1 is up-regulated in hypoxic primary human trophoblasts and that NDRG1 modulates trophoblast response to hypoxia. We initially demonstrated that the expression of NDRG1 is enhanced in primary human trophoblasts exposed to hypoxia. Importantly, we found a similar increase in NDRG1 expression in placental samples derived from either singleton gestations complicated by intrauterine growth restriction or from dizygotic twin gestation where one twin exhibited growth restriction. Having established efficient lentivirus-mediated transfection of primary human trophoblasts, we overexpressed NDRG1 in trophoblasts, which resulted in enhanced trophoblast differentiation. In contrast, lentivirus-driven short interfering RNA-mediated silencing of NDRG1 diminished trophoblast viability and differentiation. Consistent with these results, NDRG1 reduced the expression level of p53 in trophoblasts cultured in standard or hypoxic conditions. Furthermore, NDRG1 expression was regulated by the activity of SIRT1 (Sir2-like protein 1), which promotes cell survival. Together, our data indicate that NDRG1 interacts with SIRT1/p53 signaling to attenuate hypoxic injury in human trophoblasts.


Influence of antibody isotype on passive serotherapy of lymphoma.
We assessed the in vivo anti-tumor effectiveness of monoclonal antibodies of different isotypes. Starting with a hybridoma cell secreting an IgG3 anti-Thy-1.1 antibody, we isolated three variant hybridoma cell lines secreting anti-Thy-1.1 antibody of the IgG1, IgG2a, and IgG2b isotypes. Each antibody displayed identical antigen binding properties, but differed in their ability to mediate in vitro lysis of Thy-1.1+ AKR/J SL2 lymphoma cells. In assays of complement dependent cytotoxicity, the relative activity of each antibody isotype was IgG2a = IgG2b greater than IgG3 greater than IgG1. In assays of antibody-dependent cell-mediated cytotoxicity when using non-immune spleen cells as effectors, the relative activities were IgG2a greater than or equal to IgG2b greater than IgG1 greater than IgG3. Infusion of equivalent amounts of each antibody (1.5 mg) in AKR/Cum (Thy-1.2+) mice inoculated subcutaneously with 3 X 10(5) AKR/J SL2 lymphoma cells resulted in significant inhibition of tumor growth only in mice treated with IgG2a antibody. However, the antibodies were cleared at different rates, with the IgG2a antibody having the slowest clearance. When antibody doses were adjusted to achieve equivalent serum levels 24 hr after infusion, all of the antibody isotypes exhibited at least some anti-tumor activity, although IgG2a antibody was again the most effective. These studies demonstrate that the difference in anti-tumor activity between antibodies of different isotypes may result from differences both in their serum clearance rate and their ability to interact with host effector mechanisms.


An Alternative Methodological Approach for Cost-Effectiveness Analysis and Decision Making in Genomic Medicine.
Genomic Medicine aims to improve therapeutic interventions and diagnostics, the quality of life of patients, but also to rationalize healthcare costs. To reach this goal, careful assessment and identification of evidence gaps for public health genomics priorities are required so that a more efficient healthcare environment is created. Here, we propose a public health genomics-driven approach to adjust the classical healthcare decision making process with an alternative methodological approach of cost-effectiveness analysis, which is particularly helpful for genomic medicine interventions. By combining classical cost-effectiveness analysis with budget constraints, social preferences, and patient ethics, we demonstrate the application of this model, the Genome Economics Model (GEM), based on a previously reported genome-guided intervention from a developing country environment. The model and the attendant rationale provide a practical guide by which all major healthcare stakeholders could ensure the sustainability of funding for genome-guided interventions, their adoption and coverage by health insurance funds, and prioritization of Genomic Medicine research, development, and innovation, given the restriction of budgets, particularly in developing countries and low-income healthcare settings in developed countries. The implications of the GEM for the policy makers interested in Genomic Medicine and new health technology and innovation assessment are also discussed.