A real-time method to evaluate the nasal deposition and clearance of acetone in the human volunteer.
Nasal dosimetry models have become increasingly quantitative as insights into tissue deposition/clearance and computational fluid dynamics have become available. Validation of these models requires sufficient experimental data. However, investigations into respiratory deposition, particularly in human volunteers, have been historically limited due to methodological limitations. To overcome this, a method for evaluating the nasal wash-in, wash-out phenomena of a highly water-soluble compound in human volunteers was developed and characterized. This methodology was assessed using controlled human inhalation exposures to uniformly labeled [(13)C]acetone at approximately 1 ppm concentration for 30 min under different breathing maneuvers (inhale nose/exhale nose; inhale nose/exhale mouth; inhale mouth/exhale nose). A small-diameter air-sampling probe inserted in the nasopharyngeal cavity of the volunteer was connected directly to an ion-trap mass spectrometer capable of sampling every 0.8 s. A second ion-trap mass spectrometer simultaneously sampled from the volunteer's exhaled breath stream via a breath-inlet device interface. Together, the two mass spectrometers provided real-time appraisal of the [(13)C]acetone concentrations in the nasopharyngeal region and in the exhaled breath stream before, during, and after the different breathing maneuvers. The breathing cycle (depth and frequency) and heart rate were concurrently monitored throughout the exposure using a heart-rate monitor and a human plethysmograph to differentiate inhalation and exhalation. Graphical overlay of the plethysmography results with the mass spectrometer measurements show clear quantifiable differences in [(13)C]acetone levels at the nasal probe as a function of breathing maneuvers. Breath-by-breath analyses of [(13)C]acetone concentrations indicate that between 40 and 75% of the compound is absorbed upon inhalation and nearly all of that absorbed is released back into the breath stream during exhalation.


Sexually Transmitted Infections and Associated Factors in Homosexuals and Bisexuals in Granada (Spain) During the Period 2000-2015.
Sexually transmitted infections (STIs) are a major public health issue. Previous research shows the vulnerability of the homosexual and bisexual population, as well as the influence of economic, political, and cultural determinants. The aim of this study was to describe the socio-demographic healthcare profile and the main risk factors associated with STIs in homosexuals and bisexuals seen at the STI clinic in Granada (Spain) during the years 2000-2015. Infection prevalences were compared between the economic crisis period (2008-2014) and the rest of the years analysed. A cross-sectional observational and analytical study was conducted by reviewing 261 clinical records of individuals with suspected or present infection. Univariate, bivariate, and multivariate analyses were performed. 91.2% of the individuals were men, and 8.8% were women, with the mean age being 28.61 (SD = 9.35, Range = 17-74) years old. The prevailing sexual orientation identity was homosexual. 94.2% were single. The main reason for consultation was HIV. Differences in prevalence were found between crisis and non-crisis years (OR = 3.91; 95% CI = 1.73-9.19). In conclusion, their profile was that of a young, single man suspecting possible HIV infection. STI prevalence was significantly higher in the years of economic recession in comparison to the rest of the years.


Digital Support for Patients Undergoing Bariatric Surgery: Narrative Review of the Roles and Challenges of Online Forums.
The internet has become an important medium within health care, giving patients the opportunity to search for information, guidance, and support to manage their health and well-being needs. Online forums and internet-based platforms appear to have changed the way many patients undergoing bariatric surgery view and engage with their health, before and after weight loss surgery. Given that significant health improvements result from sustained weight loss, ensuring patient adherence to recommended preoperative and postoperative guidance is critical for bariatric surgery success. In a patient cohort with high information needs preoperatively, and notoriously high attrition rates postoperatively, online forums may present an underutilized method of support. The aim of this study was to conduct a narrative review focusing on the developing roles that online forums can play for patients with bariatric conditions preoperatively and postoperatively. A literature search was conducted in October-November 2019 across 5 electronic databases: Scopus, EMBASE, PsycINFO, CINAHL, and MEDLINE. Qualitative or mixed methods studies were included if they evaluated patients undergoing bariatric surgery (or bariatric surgery health care professionals) engaging with, using, or analyzing online discussion forums or social media platforms. Using thematic analysis, themes were developed from coding patterns within the data to identify the roles and challenges of online forums for patients undergoing bariatric surgery. A total of 8 studies were included in this review, with 5 themes emerging around (1) managing expectations of a new life; (2) decision making and signposting; (3) supporting information seeking; (4) facilitating connectedness: peer-to-peer social and emotional support; and (5) enabling accessibility and connectivity with health care professionals. Online forums could offer one solution to improving postoperative success by supporting and motivating patients. Future research should consider how best to design and moderate online forums for maximal effectiveness and the sharing of accurate information. The surgical multidisciplinary team may consider recommendations of online peer-support networks to complement care for patients throughout their surgical journey.


Animals in a bacterial world: opportunities for chemical ecology.
This Viewpoint article provides a brief and selective summary of research on the chemical ecology underlying symbioses between bacteria and animals. Animals engage in multiple highly specialized interactions with bacteria that reflect their long coevolutionary history. The article focuses on a few illustrative but hardly exhaustive examples in which bacterially produced small molecules initiate a developmental step with important implications for the evolution of animals, provide signals for the maturation of mammalian immune systems, and furnish chemical defenses against microbial pathogens.


[Prognostic value of SAPS II and APACHE II scales in patients with multiple organ failure syndrome during early postoperative period after oncological surgery].
The key fixed task was the following: detection, as soon as possible, of patients with a high risk of lethal outcome; an objective assessment of the condition of patients during the early postoperative period by using a quantitative evaluation (SAPS II, APACHE II); and defining of the prognostic value of SAPS II and APACHE II after oncology surgeries. The in-hospital lethality amounted to 53% in 73 patients with MOFS during the early postoperative period after oncology surgeries. The formalized (numerical) score, according to SAPS II and APACHE II, made it possible to detect patients with a higher risk of lethal outcome yet during the very first day after oncology surgeries. If the score of SAPS II or APACHE II topped 30 (on the first day after surgery), then the in-hospital lethality exceeded 50%. The information density of the SAPS II and APACHE II systems turned out to be identical, however, SAPS II appears to be more convenient in terms of practical usage since it demands the evolution of a smaller number of physiological parameters.


Reading aloud and arithmetic calculation improve frontal function of people with dementia.
Recent findings of neuroimaging studies indicate that reading aloud and arithmetic calculation activate bilateral dorsolateral prefrontal cortex of humans. The purpose of this study was to measure the effect of reading aloud and arithmetic calculation, by elderly people who were clinically diagnosed with dementia Alzheimer type, on their brain functions and activities of daily living. Sixteen experimental and 16 age- and Mini-Mental State Examination score-matched control subjects participated. The participants in the experimental group were asked to perform a training program using learning tasks in reading and arithmetic for 2-6 days a week. The function of the frontal cortex of the subjects was assessed by FAB at bedside (Frontal Assessment Battery). After 6 months of training, the FAB score of the experimental group showed a statistically significant improvement. The FAB score of the control group decreased slightly over the 6-month period, and the difference between the scores of the experimental and control groups was statistically significant. We also observed the restoration of communication and independence in the experimental group. Our results indicate that learning tasks of reading aloud and arithmetic calculation can be used for cognitive rehabilitation of dementia patients.


Quantitative trait loci that control vector competence for dengue-2 virus in the mosquito Aedes aegypti.
Quantitative trait loci (QTL) affecting the ability of the mosquito Aedes aegypti to become infected with dengue-2 virus were mapped in an F(1) intercross. Dengue-susceptible A. aegypti aegypti were crossed with dengue refractory A. aegypti formosus. F(2) offspring were analyzed for midgut infection and escape barriers. In P(1) and F(1) parents and in 207 F(2) individuals, regions of 14 cDNA loci were analyzed with single-strand conformation polymorphism analysis to identify and orient linkage groups with respect to chromosomes I-III. Genotypes were also scored at 57 RAPD-SSCP loci, 5 (TAG)(n) microsatellite loci, and 6 sequence-tagged RAPD loci. Dengue infection phenotypes were scored in 86 F(2) females. Two QTL for a midgut infection barrier were detected with standard and composite interval mapping on chromosomes II and III that accounted for approximately 30% of the phenotypic variance (sigma(2)(p)) in dengue infection and these accounted for 44 and 56%, respectively, of the overall genetic variance (sigma(2)(g)). QTL of minor effect were detected on chromosomes I and III, but these were not detected with composite interval mapping. Evidence for a QTL for midgut escape barrier was detected with standard interval mapping but not with composite interval mapping on chromosome III.


Thoracoscopic management of thoracic duct injury: Is there a place for conservatism?
Thoracic duct injury is a rare but serious complication following chest surgeries and major neck dissections. Clinically, it can present as cervical chylous fistula, chylothorax or chylopericardium. Without treatment, the mortality is up to 50% and thus, early aggressive therapy is indicated. Traditional conservative management includes low-fat diet, parenteral nutrition, careful monitoring of fluid and electrolytes, and drainage of the neck wound or chylothorax. Patients with failed conservative management require definitive treatment in the form of ligation of the thoracic duct, which has traditionally been done by thoracotomy. The advent of Video-Assisted-Thoracoscopic-Surgery (VATS) over the last decade has changed the approach towards the management of numerous chest diseases. Thoracoscopic ligation of the thoracic duct has also been reported. We report herein a case of postoperative cervical chylous fistula managed successfully by VATS thoracic duct ligation and present a systematic analysis of the English literature to highlight the current trends in the management of thoracic duct injury.


Structure of a Vaccine-Induced, Germline-Encoded Human Antibody Defines a Neutralizing Epitope on the SARS-CoV-2 Spike N-Terminal Domain.
Structural characterization of infection- and vaccination-elicited antibodies in complex with antigen provides insight into the evolutionary arms race between the host and the pathogen and informs rational vaccine immunogen design. We isolated a germ line-encoded monoclonal antibody (mAb) from plasmablasts activated upon mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and determined its structure in complex with the spike glycoprotein by electron cryomicroscopy (cryo-EM). We show that the mAb engages a previously uncharacterized neutralizing epitope on the spike N-terminal domain (NTD). The high-resolution structure reveals details of the intermolecular interactions and shows that the mAb inserts its heavy complementarity-determining region 3 (HCDR3) loop into a hydrophobic NTD cavity previously shown to bind a heme metabolite, biliverdin. We demonstrate direct competition with biliverdin and that, because of the conserved nature of the epitope, the mAb maintains binding to viral variants B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), and B.1.1.529 (omicron). Our study describes a novel conserved epitope on the NTD that is readily targeted by vaccine-induced antibody responses. IMPORTANCE We report the first structure of a vaccine-induced antibody to SARS-CoV-2 spike isolated from plasmablasts 7 days after vaccination. The genetic sequence of the antibody PVI.V6-14 suggests that it is completely unmutated, meaning that this type of B cell did not undergo somatic hypermutation or affinity maturation; this cell was likely already present in the donor and was activated by the vaccine. This is, to our knowledge, also the first structure of an unmutated antibody in complex with its cognate antigen. PVI.V6-14 binds a novel, conserved epitope on the N-terminal domain (NTD) and neutralizes the original viral strain. PVI.V6-14 also binds the newly emerged variants B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), and B.1.1.529 (omicron). Given that this antibody was likely already present in the donor prior to vaccination, we believe that this antibody class could potentially "keep up" with the new variants, should they continue to emerge, by undergoing somatic hypermutation and affinity maturation.


Intraoperative rerupture during surgical treatment of aneurysmal subarachnoid hemorrhage is not associated with an increased risk of vasospasm.
Intraoperative rerupture during open surgical clipping of cerebral aneurysms in subarachnoid hemorrhage (SAH) is a relatively frequent and potentially catastrophic occurrence. Patients who suffer rerupture have been shown to have worse outcomes at discharge compared with those who do not have rerupture. Perioperative injury likely plays a large part in the clinical worsening of these patients. However, due to the increased vessel manipulation and repeat exposure to acute hemorrhage, it is possible that secondary injury from increased incidence of vasospasm also contributes. Identifying an increased rate of vasospasm in these patients would justify early aggressive treatment with measures to prevent delayed cerebral ischemia. The authors investigated whether patients who suffer intraoperative rerupture during surgical treatment of ruptured cerebral aneurysms are at increased risk of developing vasospasm. Five hundred consecutive patients treated with open surgical clipping for SAH were reviewed, and clinical and imaging data were collected. Angiographic vasospasm was defined as vessel narrowing believed to be consistent with vasospasm on angiography. Symptomatic vasospasm was defined as angiographic vasospasm in the setting of a clinical change attributable to vasospasm. Rates of angiographic and symptomatic vasospasm among patients with and without intraoperative rerupture were compared. There were no significant differences between the groups with and without rupture with respect to age, sex, modified Fisher grade, history of hypertension, or smoking. The group with intraoperative rupture had more patients with Hunt and Hess Grade I. Angiographic vasospasm was noted in 279 (66%) of the 425 patients without rerupture compared with 49 (65%) of the 75 patients with rerupture (p = 1.0, Fisher's exact test). Symptomatic vasospasm was noted in 154 (36%) of the 425 patients without rerupture, compared with 31 (41%) of the 75 patients with rerupture (p = 0.44, Fisher's exact test). In multivariate analysis, higher modified Fisher grade was significantly predictive of vasospasm, whereas older age and male sex were protective. This study found no significant influence of intraoperative rerupture during open surgical clipping on the rate of angiographic or symptomatic vasospasm. Brief exposure to acute hemorrhage and vessel manipulation associated with rerupture events did not affect the rate of vasospasm. Risk of vasospasm was related to increased modified Fisher grade, and inversely related to age and male sex. These results do not justify early, targeted vasospasm therapy in patients with intraoperative rerupture.


Osteophagia provide giraffes with phosphorus and calcium?
The daily requirement for calcium and phosphorus by giraffes to sustain the growth and maintenance of their skeletons is large. The source of sufficient calcium is browse. The source of necessary phosphorus is obscure, but it could be osteophagia, a frequently observed behaviour in giraffes. We have assessed whether bone ingested as a result of osteophagia can be digested in the rumen. Bone samples from cancellous (cervical vertebrae) and dense bones (metacarpal shaft) were immersed in the rumens of five sheep, for a period of up to 30 days, and the effect compared to immersion in distilled water and in artificial saliva for 30 days. Distilled water had no effect on the bones. Dense bone samples were softened by exposure to the saliva and rumen fluid, but did not lose either calcium or phosphorus. In saliva and rumen fluid the cancellous bone samples also softened, and their mass and volume decreased as a result of exposure to saliva, but in neither fluid did they lose significant amounts of calcium and phosphorus. We conclude that although saliva and rumen fluid can soften ingested bones, there is an insignificant digestion of bones in the rumen.


Presence of receptors for polymerized albumin in HBsAg-containing hepatocytes and hepatoma cell line.
Recent evidence suggests that hepatitis B virions (HBV) and HBsAg particles contain receptors for polymerized human serum albumin (pHSA). We studied, by immunohistochemical techniques, the relationship between HBsAg and pHSA receptors in liver tissue from eight patients with chronic HBV infection and in a human hepatocellular carcinoma cell line (PLC/PRF/5) producing HBsAg. Both parallel sections and double fluorescent antibody staining of liver tissue demonstrated that only HBsAg-containing hepatocytes expressed pHSA receptors. The receptors could not be demonstrated in eight HBsAg negative livers. Sequential studies of PLC/PRF/5 cells revealed that pHSA and HBsAg emerged simultaneously in the cytoplasm, on the cell surface, and in the supernatant culture media. These findings indicate that pHSA receptors are closely associated with HBsAg during its synthesis and secretion by hepatocytes and suggest that the receptors are HBV-specific.


Knockdown of CRF1 receptors in the ventral tegmental area attenuates cue- and acute food deprivation stress-induced cocaine seeking in mice.
Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.


A preliminary evaluation of antihyperglycemic and analgesic activity of Alternanthera sessilis aerial parts.
Alternanthera sessilis is used by folk medicinal practitioners of Bangladesh for alleviation of severe pain. The objective of this study was to scientifically analyze the analgesic (non-narcotic) property of aerial parts of the plant along with antihyperglycemic activity. Antihyperglycemic activity was measured by oral glucose tolerance tests. Analgesic (non-narcotic) activity was determined by observed decreases in abdominal writhings in intraperitoneally administered acetic acid-induced pain model in mice. Administration of methanol extract of aerial parts led to dose-dependent and significant reductions in blood glucose levels in glucose-loaded mice. At doses of 50, 100, 200 and 400 mg per kg body weight, the extract reduced blood sugar levels by 22.9, 30.7, 45.4 and 46.1%, respectively compared to control animals. By comparison, a standard antihyperglycemic drug, glibenclamide, when administered at a dose of 10 mg per kg body weight, reduced blood glucose level by 48.9%. In analgesic activity tests, the extract at the above four doses reduced the number of abdominal writhings by 27.6, 37.9, 41.4, and 44.8%, respectively. A standard analgesic drug, aspirin, reduced the number of writhings by 31.0 and 51.7%, respectively, when administered at doses of 200 and 400 mg per kg body weight. The results validate the folk medicinal use of the plant to alleviate pain. At the same time, the antihyperglycemic activity result suggests that the plant may be a potential source for blood sugar lowering drug(s).


Efficacy of protease inhibitor monotherapy vs. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials.
The aim of this analysis was to review the evidence and update a meta-analysis evaluating the efficacy and safety results from randomized controlled trials of ritonavir-boosted protease inhibitor (PI/r) monotherapy. A PubMed/EMBASE search was conducted to find randomized trials of PI/r monotherapy vs. triple therapy in patients with HIV-1 RNA suppression at baseline (<50 HIV-1 RNA copies/mL). Rates of virological suppression were analysed using switch-equals-failure and intensification-included endpoints [intent-to-treat (ITT)]. The rate of treatment-emergent resistance mutations, neurocognitive function endpoints, and cerebrospinal fluid (CSF) HIV-1 RNA were also analysed by treatment arm. There were 2303 patients from 13 different randomized clinical trials of darunavir/r monotherapy (n = 784: MONET, MONOI, Monarch and PROTEA), lopinavir/r monotherapy (n = 829: OK pilot, OK-04, KalMo, KALESOLO, KRETA, MOST and DREAM), atazanavir/r monotherapy (n = 103: MODAT), or all three (n = 587: PIVOT). HIV-1 RNA plasma suppression was lower in the PI/r monotherapy arm compared with the triple therapy arm in the switch-equals-failure analysis [difference -8.3%; 95% confidence interval (CI) -11.9 to -4.8%], but not when intensification was included (difference 0.5%; 95% CI -2.5 to 3.6%). Rates of resistance mutations were similar between arms, as was overall neurocognitive function. PI/r monotherapy showed a higher risk of plasma HIV-1 RNA elevations. However, there was no increased risk of treatment-emergent drug resistance, neurocognitive endpoints did not differ, and HIV-1 RNA suppression rates after intensification were similar between PI/r monotherapy and triple therapy.


An evaluation of two aerosol delivery systems for rhDNase.
Increasingly, proteins are delivered to the respiratory tract as an aerosol, and clinical efficacy is dependent on optimal delivery of the protein in an intact form. The object of this study was to compare the in vivo and in vitro results of two aerosol delivery systems for the aerosolization of recombinant human deoxyribonuclease I (rhDNase) in patients with cystic fibrosis (CF). Patients with CF who were to be initiated on rhDNase were randomized either to the Hudson nebulizer and Pulmo-Aide compressor or to the Sidestream nebulizer driven by the CR50 air compressor. An in vitro study was performed in six sets of the two aerosol delivery systems. One hundred and seventy three patients were randomized in this open study, where rhDNase was administered for 7 days. Improvements in pulmonary function were observed in both groups following 1 week of therapy with rhDNase. Changes in the Sidestream/CR50 and Hudson/Pulmo-Aide groups, respectively, were: 16 and 11% for forced expiratory volume in one second (p=0.14); 12 and 10% for forced vital capacity (p=0.70); and 14 and 7% for forced expiratory flow at 25-75% of expiration (FEF(25-75)) (p=0.18). A greater proportion of patients in the Sidestream/CR50 group (58%) had a >10% response in FEF(25-75) compared to the Hudson/Pulmo-Aide group (42%; p=0.03). The Sidestream nebulizer had a faster nebulization rate (p<0.05), lower mass median diameter for the aerosol mass produced (p<0.001), higher percentage of particles in the respirable range (p<0.001) and greater respirable output (p<0.005), compared to the Hudson nebulizer. The Sidestream/CR50 combination is a quicker, more efficient system in vitro than the Hudson/Pulmo-Aide combination, whereas the in vivo study only suggested a difference. Clinically, the two systems have similar efficacy.


The role of fracture-associated soft tissue injury in the induction of systemic inflammation and remote organ dysfunction after bilateral femur fracture.
The storage of preformed cytokines in soft tissue as well as the immunocompetence of adipocytes has been reported. We hypothesized that fracture-associated soft tissue injury plays a pivotal role in the induction of systemic inflammation and remote organ dysfunction after fracture. Male C57/BL6 mice sustained either severe soft tissue injury to both thighs (STI), bilateral femur fracture with minimal soft tissue injury (Fx), or the combination of both (Fx+STI) and were euthanized 6 hours after injury. Serum cytokine concentrations were measured using the Luminex multiplexing platform, and serum ALT levels were measured with the Vitros 950 Chemistry System. Hepatic myeloperoxidase activity, a marker for polymorphonuclear cell infiltration, and hepatic IL-6 levels were determined using ELISA kits. Hepatic permeability changes were assessed via measurement of edema formation. STI as well as Fx both induced significantly elevated serum IL-6 and L-10 levels as compared with Sham animals (P < 0.05). Further, serum IL-6 and IL-10 levels were significantly higher after STI as compared with Fx (P < 0.05). Serum KC and MCP-1 levels were significantly elevated after STI but not after Fx (P < 0.05). STI as well as Fx resulted in significantly increased serum ALT levels and hepatic polymorphonuclear cell infiltration. The combination of both injuries resulted in further increased systemic inflammatory mediators as well as marked liver inflammation and dysfunction represented by significantly elevated serum ALT levels, hepatic polymorphonuclear cell infiltration, hepatic IL-6 concentrations, and hepatic edema formation as compared with Sham animals (P < 0.05). Although STI and Fx both induced a systemic inflammatory response, this was more pronounced after STI. However, the combination of both injuries (Fx+STI) was required to induce marked liver dysfunction. Our data indicate that fracture-associated soft tissue injury is a major contributor to the systemic inflammatory response after bilateral femur fracture. This should be recognized especially in multiply injured patients, who are susceptible to systemic inflammation with remote organ dysfunction.


Metabolism of [14C]monocrotaline by isolated perfused rat liver.
The metabolism of the pyrrolizidine alkaloid [14C]monocrotaline [( 14C]MCT) was examined using the in situ isolated perfused rat liver. Hepatic tissue was perfused in a recirculatory fashion for 90 min and the distribution of metabolites between the bile and perfusate was analyzed. Monocrotalic acid (MCA) was found to be the major acidic metabolite of [14C]MCT, with trace amounts of 1-formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP), and 1-hydroxymethyl-7-oxo-6,7-dihydro-5H-pyrrolizine (tentative assignment) being identified in the perfusates using GC/MS. MCT N-oxide was also identified but represented less than 4% of the perfusate 14C. The simple necine base retronecine was not present at detectable levels in the perfusion medium. A large portion of the 14C recovered from both the bile and perfusate was not extractable, under acidic or basic conditions, into organic solvents. Using fast atom bombardment MS/MS, a portion of this material was identified as a glutathione conjugate of DHP. In addition, this nonextractable material retained a portion of the radioactivity that was equivalent to the acidic fraction. Given these findings and the absence of retronecine, the major pathway for the metabolism of MCT could potentially involve the production of MCT pyrrole, which subsequently reacts with cellular nucleophiles producing MCA in addition to highly water-soluble conjugated pyrroles and possibly macromolecular adducts.


Residues in the HIV-1 capsid assembly inhibitor binding site are essential for maintaining the assembly-competent quaternary structure of the capsid protein.
Morphogenesis of infectious HIV-1 involves budding of immature virions followed by proteolytic disassembly of the Gag protein shell and subsequent assembly of processed capsid proteins (CA) into the mature HIV-1 core. The dimeric interface between C-terminal domains of CA (C-CA) has been shown to be important for both immature and mature assemblies. We previously reported a CA-binding peptide (CAI) that blocks both assembly steps in vitro. The three-dimensional structure of the C-CA/CAI complex revealed an allosteric effect of CAI that alters the C-CA dimer interface. Based on this structure, we now investigated the phenotypes of mutations in the binding pocket. CA variants carrying mutations Y169A, L211A, or L211S had a reduced affinity for CAI and were unable to form mature-like particles in vitro. These mutations also blocked morphological conversion to mature virions in tissue culture and abolished infectivity. X-ray crystallographic analyses of the variant C-CA domains revealed that these alterations induced the same allosteric change at the dimer interface observed in the C-CA/CAI complex. These results point to a role of key interactions between conserved amino acids in the CAI binding pocket of C-CA in maintaining the correct conformation necessary for mature core assembly.


Mycoplasma hyorhinis and Mycoplasma fermentans induce cell apoptosis and changes in gene expression profiles of 32D cells.
Infection of mycoplasmas has been linked to various human diseases including arthritis, pneumonia, infertility and cancer. While Mycoplasma hyorhinis and Mycoplasma fermentans have been detected in gastric adenocarcinomas, the mechanisms underlyine the pathogenesis are unknown. In this study, cell growth kinetics, Hoechst 33258 staining, DNA ladder assays, Western blotting analysis and cDNA microarray assays were performed to investigate the roles of M. hyorhinis and M. fermentans during infection of mammalian cells. Our data demonstrated that these mycoplasmas inhibid the growth of immortalised cell lines (32D and COS-7) ane tumor cell lines (HeLa and AGS). In addition, the infection of the 32D cell line with M. hyorhinis and M. fermentans induced compression of the nucleus, degradation of the cell genome and dysregulation of the expression of genes related to proliferation, apoptosis, tumorigenesis, signaling pathway and metabolism. Apoptosis related proteins Bcl-2, Bid and p53 were down-regulated, Fas was up-regulated and Bax was dysregulated in mycoplasma-infected 32D cells. Together, our data demonstrated that infection of mycoplasmas inhibitd cele growts through modification of gene expression profiles and post-translation modification of proliferation and apoptosis related proteins.


Gender and smoking-related risk of lung cancer. The Copenhagen Center for Prospective Population Studies.
Our aim was to compare risk of lung cancer associated with smoking by gender and histologic type. A total of 30,874 subjects, 44% women, from three prospective population-based studies with initial examinations between 1964 and 1992 were followed until 1994 through the National Cancer Registry. There were 867 cases of lung cancer, 203 among women and 664 among men. Rates among female and male never-smokers were similar, although confidence intervals around rates were wide. Rate ratios (RRs) increased with number of pack-years for both men and women to a maximum of approximately 20 in inhaling smokers with more than 60 pack-years of tobacco exposure. RRs did not differ much between men and women: adjusted for pack-years, age, and study population, the ratio between female and male smokers' RRs of developing lung cancer was 0.8 (95% confidence interval = 0.3-2.1). All histologic types were associated with smoking, with the largest RR seen for squamous cell carcinoma and anaplastic carcinoma. This prospective population-based study does not confirm previous reports from case-control studies of a higher relative risk in women than in men for lung cancer associated with smoking.


Targeting Gut Microbial Biofilms-A Key to Hinder Colon Carcinogenesis?
Colorectal cancer (CRC) is a global public health issue which poses a substantial humanistic and economic burden on patients, healthcare systems and society. In recent years, intestinal dysbiosis has been suggested to be involved in the pathogenesis of CRC, with specific pathogens exhibiting oncogenic potentials such as Fusobacterium nucleatum, Escherichia coli and enterotoxigenic Bacteroides fragilis having been found to contribute to CRC development. More recently, it has been shown that initiation of CRC development by these microorganisms requires the formation of biofilms. Gut microbial biofilm forms in the inner colonic mucus layer and is composed of polymicrobial communities. Biofilm results in the redistribution of colonic epithelial cell E-cadherin, increases permeability of the gut and causes a loss of function of the intestinal barrier, all of which enhance intestinal dysbiosis. This literature review aims to compile the various strategies that target these pathogenic biofilms and could potentially play a role in the prevention of CRC. We explore the potential use of natural products, silver nanoparticles, upconverting nanoparticles, thiosalicylate complexes, anti-rheumatic agent (Auranofin), probiotics and quorum-sensing inhibitors as strategies to hinder colon carcinogenesis via targeting colon-associated biofilms.


Glutamine metabolism and function in relation to proline synthesis and the safety of glutamine and proline supplementation.
At normal intakes, dietary glutamine and glutamate are metabolized by the small intestine and essentially all glutamine within the body is synthesized de novo through the action of glutamine synthetase. The major sites of net glutamine synthesis are skeletal muscle, lung, and adipose tissue and, under some conditions, the liver. In addition to the small intestine, where glutamine is the major respiratory fuel, other sites of net glutamine utilization include the cells of the immune system, the kidneys, and the liver. The intestine expresses pyrroline 5-carboxylate (P5C) synthase, which means that proline is an end product of intestinal glutamine catabolism. Proline can also be synthesized from ornithine and the exact contribution of the 2 pathways is not certain. Infusion of proline i.v. to increase circulating concentrations is associated with increased proline oxidation and decreased proline synthesis. In contrast, conditions of proline insufficiency, after feeding low-proline diets or in response to high rates of proline catabolism in burn patients, do not result in increased proline synthesis. Glutamine supplementation is widespread and up to 0.57-0.75 g.kg(-1).d(-1) is well tolerated. Similarly, the only study of proline supplementation, in which patients with gyrate atrophy were given 488 mg.kg(-1).d(-1), reported no deleterious side effects. In the absence of controlled trials, it is currently not possible to estimate a safe upper limit for either of these 2 amino acids.


Synthesis, molecular structure, and validation of metalloprobes for assessment of MDR1 P-glycoprotein-mediated functional transport.
The human genome is known to consist of 49 ATP-binding cassette (ABC) transporter genes. Among these ABC proteins, overexpression of multidrug resistance (MDR1) P-glycoprotein (Pgp/ABCB1) is the best characterized barrier to successful chemotherapeutic treatments, impacts pharmacokinetics of numerous recognized drugs, and is also quickly emerging as an important target in the development of neurodegenerative diseases. Therefore, there exists an urgent need to seek radiopharmaceuticals, incorporated with generator-produced radionuclides to assist their widespread deployment, for noninvasive assessment of Pgp-mediated functional transport activity in vivo. gallium(III) complexes (5a and 5b) possessing octahedral geometry were synthesized, analytically characterized, and evaluated for their potential to serve as probes of Pgp-mediated functional transport activity in cellulo and in vivo. While unlabeled compounds (5a and 5b) were examined via cell cytotoxicity assays, the (67)Ga-labeled counterparts (6a and 6b) were evaluated via cell transport studies and quantitative biodistribution studies in mdr1a/1b((-/-)) gene-deleted mice and their wild-type (WT) counterparts. cytotoxicity data of 5a and 5b displayed profiles modified by the expression of Pgp in drug-resistant cells. (67)Ga-metalloprobes (6a and 6b) showed high accumulation in human epidermal carcinoma drug-sensitive KB-3-1 cells (Pgp-), human breast carcinoma MCF-7 (Pgp-) cells; an inhibitor (LY335979, 1 microM) induced accumulation in multidrug resistant (MDR, Pgp+) KB-8-5, KB-8-5-11 cells, and stably transfected MCF-7/MDR1 cells, thus demonstrating their ability to interrogate Pgp-mediated functional transport activity in cellulo. In mdr1a/1b((-/-)) gene-deleted mice, the (67)Ga-metalloprobe (6b) showed 8-fold greater brain uptake and retention compared with WT counterparts and no significant difference in blood pharmacokinetics. molecular imaging of the functional transport activity of MDR1 Pgp (ABCB1) with (67/68)Ga-metalloprobes could enable non-invasive monitoring of the blood-brain barrier, tumors, and tissues in vivo.


Effect of cardiac arrest with aortic cross-clamping during left ventricular assist device implantation.
Some patients who undergo continuous-flow left ventricular assist device (CF-LVAD) implantation require concomitant procedures that can be performed with or without cardiac arrest under aortic cross-clamping (AXC). Procedures normally performed with cardiac arrest are sometimes avoided or performed without cardiac arrest because it may be detrimental to right heart function. However, the effects of cardiac arrest on patients with advanced heart failure necessitating CF-LVAD support have not been thoroughly studied. We examined our single-centre experience to determine whether cardiac arrest during CF-LVAD implantation was associated with worse patient outcomes. From November 2003 to March 2016, a total of 526 patients with chronic end-stage heart failure underwent primary CF-LVAD implantation. Preoperative demographics, postoperative complications and mortality rates were compared between patients who required cardiac arrest with AXC (n = 50) and those who did not (n = 476). The most frequently performed procedure requiring AXC was aortic valve closure (n = 23, 26.1%). Although the AXC group had longer cardiopulmonary bypass times (P < 0.01), long-term (5-year) survival was similar in AXC and non-AXC patients (P = 0.13). Also, postoperative right heart failure (P = 0.15) and neurological dysfunction (P = 0.89) rates were not significantly different between the 2 groups. Cox proportional hazards analysis showed that cardiac arrest with AXC was not an independent predictor of mortality (hazard ratio, 0.89; P = 0.73). Cardiac arrest with AXC during CF-LVAD implantation did not negatively affect long-term survival or the incidence of right ventricular failure or stroke. These findings should be considered in deciding surgical strategies. Additional investigation may be warranted to further understand the effects of cardiac arrest during LVAD implantation.


Mindfulness and motivational interviewing: two candidate methods for promoting self-management.
There is no conclusive evidence about the way to a promote behavior change in self-management programs for patients with chronic obstructive pulmonary disease (COPD). The latter is a significant knowledge gap as there is a need to promote a sustained effect in interventions like Pulmonary Rehabilitation or Supporting Programs. Embracing patient's values seems to be a key ingredient to ignite genuine motivation for behavior change. This manuscript describes two pilot qualitative studies carried out in patients with severe COPD aimed to engage the patient inner experience and promote self-management: a trial testing motivational interviewing (MI) as one style of helping patients with severe COPD make changes in their behavior and second a trial testing a mindfulness-based intervention. The MI study consisted of a 3-month program of weekly coaching phone calls after one face-to-face visit. The following themes were outstanding: patients value the supportive communication with coach and believe the MI-based coaching created increased level of awareness and accountability. They perceived an increase in physical activity and reported "feeling better" or other benefits not directly related to exercise. The Mindfulness for Health Program was a mandatory 8-week program that consisted on 2-hour classes aimed to cultivate nonjudgmental attention in the moment (through different meditative practices and sharing) plus monthly face-to-face encounters aimed to sustain practice and sharing of life experiences for 1 year. The following themes (at 1 year) were outstanding: appreciating life by seeing hardships as opportunities, valuing the self through compassion and awareness, cultivating connectedness with others, acquiring joy, and adopting healthy behaviors. In the search for the "holy grail" for self-management programs that can promote a behavior change, mindfulness and MI seem promising for cultivating a way to live a life in which people are fully present and consciously agree with.


Thermosporothrix narukonensis sp. nov., belonging to the class Ktedonobacteria, isolated from fallen leaves on geothermal soil, and emended description of the genus Thermosporothrix.
A thermophilic, Gram-stain-positive, spore-forming bacterium that formed branched vegetative and aerial mycelia was isolated from fallen leaves on geothermal soil. This strain, designated F4T, grew at temperatures between 30 and 60 °C; optimum growth temperature was 50 °C, whereas no growth was observed below 28 °C or above 65 °C. The pH range for growth was 4.9-9.5; the pH for optimum growth was 7.0, but no growth was observed at pH below 4.4 or above 10.0. Strain F4T was able to hydrolyse polysaccharides such as cellulose, xylan, chitin and starch. The G+C content in the DNA of strain F4T was 52.5 mol%. The major fatty acid was iso-C17 : 0 and the major menaquinone was MK-9 (H2). The cell wall of strain F4T contained glutamic acid, serine, glycine, alanine and ornithine in a molar ratio of 1.0:1.5:1.4:1.8:0.7. The polar lipids of this strain consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, one unknown phospholipid, three unknown glycolipids and two unknown lipids. The cell-wall sugar was mannose. Detailed phylogenetic analysis based on 16S rRNA gene sequences indicated that strain F4T belongs to the genus Thermosporothrix, and that it was related most closely to Thermosporothrix hazakensis SK20-1T (98.7 % similarity). DNA-DNA hybridization showed relatedness values of less than 15 % with the type strain of Thermosporothrix hazakensis. On the basis of phenotypic features and phylogenetic position, strain F4T is considered to represent a novel species, Thermosporothrix narukonensis sp. nov. The type strain is F4T(=NBRC 111777T=BCCM/LMG 29329T).


Reciprocal synergy between Escherichia coli and Bacteroides fragilis in an intra-abdominal infection model.
The synergic relationship between Escherichia coli and Bacteroides fragilis was examined in a model of intra-abdominal abscess formation. The addition of B. fragilis to E. coli in the fibrin clot inoculum increased abscess weight and residual numbers of E. coli in the abscess at 7 days. In a reciprocal fashion, E. coli was capable of enhancing B. fragilis persistence in abscesses. Neither heat-killed E. coli nor heat-killed B. fragilis was able to mimic the synergic effect of its live counterpart. Furthermore, B. fragilis culture filtrate was unable to reproduce the ability of live B. fragilis to act synergically with E. coli. For B. fragilis to act synergically with E. coli, it had to be inoculated locally with E. coli in the peritoneal cavity, indicating that an effect on systemic resistance by B. fragilis was an unlikely mechanism for the production of bacterial synergy. These studies suggest that the synergic relationship between bacteria in polymicrobial infections is a complex one, resulting from intimate interactions between bacteria and the host in the local milieu of the infection.


Diabetes in the Medicare aged population, 2004.
The Medicare Current Beneficiary Survey (MCBS) contains a wealth of information on the health status of Medicare beneficiaries. In particular, the 2004 MCBS included a series of questions about diabetes care for those who reported they had the condition, and diabetes screening for those who said they did not. This highlight reviews some of the characteristics of the diabetic population compared to the non-diabetic population.


[The use of point massage in patients with circulatory encephalopathy].
The comprehensive studies involving rheoencephalography and tetrapolar thoracic rheography made in 120 patients with dyscirculatory encephalopathy (DE) indicated that pointed massage caused a noticeable rearrangement of hemodynamic processes, which depended on the clinical cause of the disease and the baseline status of the circulatory system. This makes it possible to consider pointed massage as a therapeutical factor aimed at correcting cerebral circulation, which is indicated particularly in DE patients having a history of transitory ischemic attacks in the vertebrobasilar bed.


Correlation of glutamate levels in the anterior cingulate cortex with self-reported impulsivity in patients with borderline personality disorder and healthy controls.
Dysfunction and deficits in the structure of the anterior cingulate cortex have been reported in borderline personality disorder (BPD). To our knowledge, there is only 1 published study to date investigating anterior cingulate cortex metabolism in subjects with BPD and co-occurring attention-deficit/hyperactivity disorder using proton magnetic resonance spectroscopy. Impulsivity is a key feature of BPD and can be related to anterior cingulate cortex function. To investigate whether anterior cingulate cortex metabolism may be altered in BPD and correlates with BPD pathology. Cross-sectional proton magnetic resonance spectroscopy study. Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany. Thirty unmedicated female subjects meeting DSM-IV criteria for BPD and 31 age-matched healthy female control participants. Neurometabolite concentrations in the anterior cingulate cortex and correlation of glutamate levels with self-reported measures of impulsivity and severity of borderline symptoms. Significantly higher levels of glutamate in the anterior cingulate cortex were found in subjects with BPD as compared with healthy controls. A positive correlation between glutamate concentration and the Barratt Impulsiveness Scale total score as well as between glutamate concentration and the subscore for cognitive impulsivity were observed irrespective of diagnosis. We also found a positive correlation between glutamate concentrations and dissociation as well as between glutamate concentration and subscores of the Borderline Symptom List in the patient group. Our results support the hypothesis that higher glutamate concentration in the anterior cingulate cortex is associated with both severity of BPD symptoms and subjective impulsivity ratings, the latter independent of BPD. Further studies should confirm the association between enhanced glutamate concentration in the anterior cingulate cortex and behavioral measures of impulsivity.


Selective inhibition of glucose oxidation by triethyltin in rat brain in vivo.
Results are reported of a comparative study in vivo of the metabolism of [2-(14)C]-glucose and [1-(14)C]acetate in brains of rats intoxicated with triethyltin sulphate. The incorporation of (14)C from glucose into glutamate, glutamine, gamma-aminobutyrate and aspartate was greatly decreased. The incorporation of (14)C from acetate into these amino acids was unaffected. The experimental data indicated that the main action of triethyltin was to decrease the rate at which pyruvate formed from glucose is oxidized. Glycolysis was not inhibited. Changes in glucose metabolism in the brain are shown not to be directly due to hypothermia. Some of the advantages of measuring the labelling of intermediates at very short time intervals after the injection of the labelled glucose are demonstrated.


Circulating microRNAs as Diagnostic Markers in Primary Aldosteronism.
Primary aldosteronism (PA) is a common and highly treatable condition, usually resulting from adrenocortical tumorous growth or hyperplasia. PA is currently underdiagnosed owing to its complex and protracted diagnostic procedures. A simplified biomarker-based test would be highly valuable in reducing cardiovascular morbidity and mortality. Circulating microRNAs are emerging as potential biomarkers for a number of conditions due to their stability and accessibility. PA is known to alter microRNA expression in adrenocortical tissue; if these changes or their effects are mirrored in the circulating miRNA profile, then this could be exploited by a diagnostic test. However, the reproducibility of studies to identify biomarker-circulating microRNAs has proved difficult for other conditions due to a series of technical challenges. Therefore, any studies seeking to definitively identify circulating microRNA biomarkers of PA must address this in their design. To this end, we are currently conducting the circulating microRNA arm of the ongoing ENS@T-HT study. In this review article, we present evidence to support the utility of circulating microRNAs as PA biomarkers, describe the practical challenges to this approach and, using ENS@T-HT as an example, discuss how these might be overcome.


Nucleoside diphosphatase and glycosyltransferase activities can localize to different subcellular compartments in Schizosaccharomyces pombe.
Nucleoside diphosphates generated by glycosyltransferases in the fungal, plant, and mammalian cell secretory pathways are converted into monophosphates to relieve inhibition of the transferring enzymes and provide substrates for antiport transport systems by which the entrance of nucleotide sugars from the cytosol into the secretory pathway lumen is coupled to the exit of nucleoside monophosphates. Analysis of the yeast Schizosaccharomyces pombe genome revealed that it encodes two enzymes with potential nucleoside diphosphatase activity, Spgda1p and Spynd1p. Characterization of the overexpressed enzymes showed that Spgda1p is a GDPase/UDPase, whereas Spynd1p is an apyrase because it hydrolyzed both nucleoside tri and diphosphates. Subcellular fractionation showed that both activities localize to the Golgi. Individual disruption of their encoding genes did not affect cell viability, but disruption of both genes was synthetically lethal. Disruption of Spgda1+ did not affect Golgi N- or O-glycosylation, whereas disruption of Spynd1+ affected Golgi N-mannosylation but not O-mannosylation. Although no nucleoside diphosphatase activity was detected in the endoplasmic reticulum (ER), N-glycosylation mediated by the UDP-Glc:glycoprotein glucosyltransferase (GT) was not severely impaired in mutants because first, no ER accumulation of misfolded glycoproteins occurred as revealed by the absence of induction of BiP mRNA, and second, in vivo GT-dependent glucosylation monitored by incorporation of labeled Glc into folding glycoproteins showed a partial (35-50%) decrease in Spgda1 but was not affected in Spynd1 mutants. Results show that, contrary to what has been assumed to date for eukaryotic cells, in S. pombe nucleoside diphosphatase and glycosyltransferase activities can localize to different subcellular compartments. It is tentatively suggested that ER-Golgi vesicle transport might be involved in nucleoside diphosphate hydrolysis.


High resolution X-ray structure of dTDP-glucose 4,6-dehydratase from Streptomyces venezuelae.
Desosamine is a 3-(dimethylamino)-3,4,6-trideoxyhexose found in some macrolide antibiotics. In Streptomyces venezuelae, there are seven genes required for the biosynthesis of this unusual sugar. One of the genes, desIV, codes for a dTDP-glucose 4,6-dehydratase, which is referred to as DesIV. The reaction mechanisms for these types of dehydratases are quite complicated with proton abstraction from the sugar 4'-hydroxyl group and hydride transfer to NAD+, proton abstraction at C-5, and elimination of the hydroxyl group at C-6 of the sugar, and finally return of a proton to C-5 and a hydride from NADH to C-6. Here we describe the cloning, overexpression, and purification, and high resolution x-ray crystallographic analysis to 1.44 A of wild-type DesIV complexed with dTDP. Additionally, for this study, a double site-directed mutant protein (D128N/E129Q) was prepared, crystallized as a complex with NAD+ and the substrate dTDP-glucose and its structure determined to 1.35 A resolution. In DesIV, the phenolate group of Tyr(151) and O(gamma) of Thr(127) lie at 2.7 and 2.6 A, respectively from the 4'-hydroxyl group of the dTDP-glucose substrate. The side chain of Asp(128) is in the correct position to function as a general acid for proton donation to the 6'-hydroxyl group while the side chain of Glu(129) is ideally situated to serve as the general base for proton abstraction at C-5. This investigation provides further detailed information for understanding the exquisite chemistry that occurs in these remarkable enzymes.


Transcriptome study of receptive endometrium in overweight and obese women shows important expression differences in immune response and inflammatory pathways in women who do not conceive.
Obesity and being overweight are growing worldwide health problems that also affect women of reproductive age. They impair women's fertility and are associated with lower IVF success rates. The mechanism by which increased body weight disrupts fertility has not yet been established. One possibility is that it affects the process of embryo implantation on the endometrial level. The purpose of our study was to determine the differences in enriched biological pathways in the endometrium of overweight and obese women undergoing IVF procedures. For this purpose, 14 patients (5 pregnant, 9 non-pregnant) were included in the study. Endometrial samples were obtained during the window of implantation and RNA sequencing was performed. There were no differences in general patient's and IVF cycle characteristics between pregnant and non-pregnant women. In the endometrial samples of women who did not conceive, pathways related to the immune response, inflammation, and reactive oxygen species production were over-expressed. Our findings show that the reason for implantation failure in overweight and obese women could lie in the excessive immune and inflammatory response at the endometrial level.


Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma.
To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m2 intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m2 IV on day 1; vincristine, 1.4 mg/m2 IV on day 1; and prednisone, 40 mg/m2 orally on days 1 through 5 every 4 weeks). Results Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.


Spectral phenotyping of embryonic development reveals integrative thermodynamic responses.
Energy proxy traits (EPTs) are a novel approach to high dimensional organismal phenotyping that quantify the spectrum of energy levels within different temporal frequencies associated with mean pixel value fluctuations from video. They offer significant potential in addressing the phenotyping bottleneck in biology and are effective at identifying lethal endpoints and measuring specific functional traits, but the extent to which they might contribute additional understanding of the phenotype remains unknown. Consequently, here we test the biological significance of EPTs and their responses relative to fundamental thermodynamic principles. We achieve this using the entire embryonic development of Radix balthica, a freshwater pond snail, at different temperatures (20, 25 & 30 °C) and comparing responses against predictions from Arrhenius' equation (Q10 = 2). We find that EPTs are thermally sensitive and their spectra of frequency response enable effective high-dimensional treatment clustering throughout organismal development. Temperature-specific deviation in EPTs from thermodynamic predictions were evident and indicative of physiological mitigation, although they differed markedly in their responses from manual measures. The EPT spectrum was effective in capturing aspects of the phenotype predictive of biological outcomes, and suggest that EPTs themselves may reflect levels of energy turnover. Whole-organismal biology is incredibly complex, and this contributes to the challenge of developing universal phenotyping approaches. Here, we demonstrate the biological relevance of a new holistic approach to phenotyping that is not constrained by preconceived notions of biological importance. Furthermore, we find that EPTs are an effective approach to measuring even the most dynamic life history stages.


New developments in the treatment of nontuberculous mycobacterial (NTM) disease.
Until recently, therapy for most Nontuberculous Mycobacterial (NTM) disease, especially disease caused by Mycobacterium avium-complex (MAC), has been difficult and frustrating. The introduction of the newer macrolides (clarithromycin and azithromycin) has significantly added to the efficacy of regimens for both disseminated and pulmonary MAC disease. Clinical activity of these agents is lost when a MAC isolate develops in-vitro resistance that is facilitated by use of the macrolides as single agents. These valuable drugs should, therefore, never be used as single agents for the treatment of disseminated or pulmonary MAC disease. The newer macrolides also show promise for the treatment of other NTM infections such as those caused by M. abscessus, M. fortuitum, M. chelonae, M. xenopi, M. marinum, M. haemophilum, and M. genavense. Rifabutin, a derivative of rifamycin S, is an effective agent for prophylaxis against disseminated MAC and may have utility for treatment of pulmonary and disseminated MAC disease. Interactions between clarithromycin and rifamycin may alter efficacy of the macrolide and enhance toxicity of rifabutin. Although therapy of many NTM infections remains difficult with somewhat unpredictable results, the introduction of newer drugs, particularly the macrolides, has appreciably improved a previously dismal outlook for successful therapy.


EXCI-CEST: Exploiting pharmaceutical excipients as MRI-CEST contrast agents for tumor imaging.
Chemical Exchange Saturation Transfer (CEST) approach is a novel tool within magnetic resonance imaging (MRI) that allows visualization of molecules possessing exchangeable protons with water. Many molecules, employed as excipients for the formulation of finished drug products, are endowed with hydroxyl, amine or amide protons, thus can be exploitable as MRI-CEST contrast agents. Their high safety profiles allow them to be injected at very high doses. Here we investigated the MRI-CEST properties of several excipients (ascorbic acid, sucrose, N-acetyl-d-glucosamine, meglumine and 2-pyrrolidone) and tested them as tumor-detecting agents in two different murine tumor models (breast and melanoma cancers). All the investigated molecules showed remarkable CEST contrast upon i.v. administration in the range 1-3ppm according to the type of mobile proton groups. A marked increase of CEST contrast was observed in tumor regions up to 30min post injection. The combination of marked tumor contrast enhancement and lack of toxicity make these molecules potential candidates for the diagnosis of tumors within the MRI-CEST approach.


Asthma in adolescents living in the inner city.
Asthma disproportionately affects minority individuals living in poor urban areas, particularly children and adolescents aged 5-17 years. A variety of factors are likely to account for asthma disparities in inner-city populations. Housing characteristics increase the risk of exposure to potential asthma triggers. Environmental risk factors have been studied extensively and cockroach allergen has emerged as an important determinant of asthma morbidity. Neighborhood factors also appear to contribute to the problem of inner-city asthma. Various novel treatment intervention strategies have demonstrated encouraging results. This article reviews environmental factors and recently published strategies to reduce morbidity in this vulnerable population.


Performance of diabetic rat hearts: effects of anoxia and increased work.
An isolated perfused working rat heart preparation was used to assess the effect of alloxan-induced diabetes on myocardial performance. Ventricular performance was assessed under different aortic afterload, isoproterenol-stimulated and anoxic conditions. Basal left ventricular pressure development and rate of rise of ventricular pressure were depressed in hearts from diabetic animals. Neither coronary flow nor cardiac output were affected by diabetes. The dose and temporal responses to an infusion of isoproterenol were unaltered in diabetic hearts. Isoproterenol increased coronary flow by 50% and elevated ventricular pressure, dP/dt, and cardiac output by two- to threefold. Anoxia depressed ventricular pressure to below 20% of control within 5 min in both diabetic and normal hearts. Reoxygenation after 10 min of anoxia produced equivalent recovery in both groups working against a 52-mmHg aortic afterload, whereas recovery after 20 or 30 min of anoxia, was depressed in diabetic hearts. Elevating aortic afterload decreased performance of diabetic hearts and decreased their ability to recover from a 10-min anoxic exposure. Many of these observed differences in mechanical performance of diabetic hearts can be overcome by high glucose or insulin in the perfusion media.


Functional Analysis of the Coronary Heart Disease Risk Locus on Chromosome 21q22.
Background. The coronary heart disease (CHD) risk locus on 21q22 (lead SNP rs9982601) lies within a "gene desert." The aim of this study was to assess if this locus is associated with CHD risk factors and to identify the functional variant(s) and gene(s) involved. Methods. A phenome scan was performed with UCLEB Consortium data. Allele-specific protein binding was studied using electrophoretic mobility shift assays. Dual-reporter luciferase assays were used to assess the impact of genetic variation on expression. Expression quantitative trait analysis was performed with Advanced Study of Aortic Pathology (ASAP) and Genotype-Tissue Expression (GTEx) consortium data. Results. A suggestive association between QT interval and the locus was observed (rs9982601 p = 0.04). One variant at the locus, rs28451064, showed allele-specific protein binding and its minor allele showed 12% higher luciferase expression (p = 4.82 × 10-3) compared to the common allele. The minor allele of rs9982601 was associated with higher expression of the closest upstream genes (SLC5A3 1.30-fold increase p = 3.98 × 10-5; MRPS6 1.15-fold increase p = 9.60 × 10-4) in aortic intima media in ASAP. Both rs9982601 and rs28451064 showed a suggestive association with MRPS6 expression in relevant tissues in the GTEx data. Conclusions. A candidate functional variant, rs28451064, was identified. Future work should focus on identifying the pathway(s) involved.


The power of social connection and support in improving health: lessons from social support interventions with childbearing women.
Social support interventions have a somewhat chequered history. Despite evidence that social connection is associated with good health, efforts to implement interventions designed to increase social support have produced mixed results. The aim of this paper is to reflect on the relationship between social connectedness and good health, by examining social support interventions with mothers of young children and analysing how support was conceptualised, enacted and valued, in order to advance what we know about providing support to improve health. CONTEXT AND APPROACH: First, we provide a brief recent history of social support interventions for mothers with young children and we critically examine what was intended by 'social support', who provided it and for which groups of mothers, how support was enacted and what was valued by women. Second, we examine the challenges and promise of lay social support approaches focused explicitly on companionship, and draw on experiences in two cluster randomised trials which aimed to improve the wellbeing of mothers. One trial involved a universal approach, providing befriending opportunities for all mothers in the first year after birth, and the other a targeted approach offering support from a 'mentor mother' to childbearing women experiencing intimate partner violence. Interventions providing social support to mothers have most often been directed to women seen as disadvantaged, or 'at risk'. They have also most often been enacted by health professionals and have included strong elements of health education and/or information, almost always with a focus on improving parenting skills for better child health outcomes. Fewer have involved non-professional 'supporters', and only some have aimed explicitly to provide companionship or a listening ear, despite these aspects being what mothers receiving support have said they valued most. Our trial experiences have demonstrated that non-professional support interventions raise myriad challenges. These include achieving adequate reach in a universal approach, identification of those in need of support in any targeted approach; how much training and support to offer befrienders/mentors without 'professionalising' the support provided; questions about the length of time support is offered, how 'closure' is managed and whether interventions impact on social connectedness into the future. In our two trials what women described as helpful was not feeling so alone, being understood, not being judged, and feeling an increased sense of their own worth. Examination of how social support has been conceptualised and enacted in interventions to date can be instructive in refining our thinking about the directions to be taken in future research. Despite implementation challenges, further development and evaluation of non-professional models of providing support to improve health is warranted.


Identification of T-2 toxin in moldy corn associated with a lethal toxicosis in dairy cattle.
Over a 5-month period during the winter of 1970-71, 20% of the lactating Holstein cows in a Wisconsin dairy herd died after prolonged ingestion of a diet containing 60% moldy corn infested with Fusarium tricinctum (2 x 10(5) propagules per g of moldy corn). Ethyl acetate extracts of the ground dried corn induced severe dermal reactions when applied to the skin of shaved 60-g albino rats and killed four of five 100-g rats that were force fed 1 ml in 2 ml of pure corn oil. T-2 toxin (3-hydroxy-4, 15-diacetoxy-8-[3-methylbutyryloxy]-12, 13-epoxy-Delta(9)-trichothecene) at concentrations of 2 mg per kg of dry corn was identified in purified extracts of the moldy corn by means of gas-liquid chromatography and mass spectrometry. This concentration of T-2 toxin in the moldy feed and the nature of the toxic effects observed strongly suggest a major causal relationship.


An atrophic, telangiectatic patch at the distal border of the tongue: a mucous membrane manifestation of xeroderma pigmentosum.
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by clinical and cellular sensitivity, pigmentary changes, and early development of malignancies in sun-exposed mucocutaneous and ocular structures due to a defective ability to repair intracellular DNA damage. Individuals with XP also have a greater frequency of oral cancer, particularly squamous cell carcinoma of the anterior third of the tongue. The current study reports four cases of XP that exhibited a characteristic crescent-shaped, atrophic, telangiectatic area on the distal border of the tongue and correlates this lesion with the development of tumors at this site during follow-up. The tongue lesion was photographed and biopsied in the four patients. During routine follow-up visits, new biopsies were performed if additional tongue lesions were observed. The studied lesions were similar in the four patients. During follow-up, squamous cell carcinoma developed in one patient and pyogenic granuloma developed in three patients and was relapsing in one. The lesion remained stable in one patient during the study. The atrophic and telangiectatic patches probably occur because of chronic sun damage to the exposed portion of the tongue, and this area has a high predisposition for the development of benign and malignant tumors.


Incidence of end-stage renal disease: magnitude of the problem and its implications.
Data on incidence and prevalence rates of end-stage renal disease (ESRD) from selected countries including Saudi Arabia are provided. Current data from this country suggest that the incidence of treated ESRD (t-ESRD) in the age-group 0-20 years is 14 per million population (PMP) while the combined incidence for all ages is 240 PMP. The cost of management of the patients is staggering. In Japan, it has been estimated that the projected prevalence of t-ESRD will be 1111 PMP needing an estimated budget of US $ 5.8 billion per year for their management. Globally, more than US $ 50 billion would be needed per year with the presently available treatment modalities. This financial liability might make "Health for all by the year 2000" a myth unless some cheaper method of treatment is made available. Vigorous research is needed towards identifying and prioritizing vulnerable groups for ESRD by identifying and properly managing at-risk groups. These include patients with diabetes mellitus and hypertension as well as patients with indicators like proteinuria and obstructive uropathy. Cheaper modes of renal replacement therapy should be sought. Interesting ideas such as induction of diarrhea for amelioration of renal failure need to be explored further as also the use of the patient's own intestine as a medium for molecular exchange.


Regulation and distribution of European sea bass perforins point to their role in the adaptive cytotoxic response against NNV.
Cell-mediated cytotoxicity is a complex immune mechanism that involves the release of several killing molecules, being perforin (PRF) one of the most important effector players. Perforin is synthesized by T lymphocytes and natural killer cells in mammals and responsible for the formation of pores on the target cell membrane during the killing process. Although perforin has been extensively studied in higher vertebrates, this knowledge is very limited in fish. Therefore, in this study we have identified four prf genes in European sea bass (Dicentrarchus labrax) and evaluated their mRNA levels. All sea bass prf genes showed the typical and conserved domains of its human orthologue and were closely clustered by the phylogenetic analysis. In addition, all genes showed constitutive and ubiquitous tissular expression, being prf1.9 gene the most highly expressed in immune tissues. Subsequently, in vitro stimulation of head-kidney (HK) cells with phytohemagglutinin, a T-cell activator, showed an increase of all prf gene levels, except for prf1.3 gene. European sea bass HK cells increased the transcription of prf1.2 and prf1.9 during the innate cell-mediated cytotoxic activity against xenogeneic target cells. In addition, sea bass infected with nodavirus (NNV) showed a similar expression pattern of all prf in HK and brain at 15 days post-infection, except for prf1.3 gene and in the gonad. Finally, the use of a polyclonal antibody against PRF1.9 showed an increase of positive cells in HK, brain and gonad from NNV-infected fish. Taken together, the data seem to indicate that all prf genes, except prf1.3, appear to be involved in the European sea bass immunity, and probably in the cell-mediated cytotoxic response, with PRF1.9 playing the most important role against nodavirus. The involvement of the PRFs and the CMC activity in the vertical transmission success of the virus is also discussed.


Aryl hydrocarbon receptor control of a disease tolerance defence pathway.
Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.


Current Diagnosis and Management of Abetalipoproteinemia.
Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutations in the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fat-soluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, and failure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety of symptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular (spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to the development of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications and improve the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis are awaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, and management of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support from the Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) <15 mg/dL and apoB <15 mg/dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.


Long-term outcomes of I-Stop TOMS™ male sling implantation for post-prostatectomy incontinence management.
To report long-term outcomes after I-Stop TOMS™ implantation for PPI. A retrospective evaluation was conducted in three tertiary reference centers. All consecutive patients implanted with an I-Stop TOMS™ sling between 2007 and 2012 for mild to moderate PPI (24-hour Pad test<400g) without history of pelvic radiation therapy were included. Evaluation had been conducted preoperatively, at one and six months postoperative and yearly thereafter. The main outcome criterion was the number of pads per day. Secondary criteria were International Consultation on Incontinence Questionnaire (ICIQ), SF-36 questionnaire, and complications. A hundred patients were evaluated with a median follow-up of 58months [19-78]. Pad use was significantly reduced and quality of life improved at last follow-up (P<0.0001). The percentage of patients dry and socially continent (0 or 1 pad) were 40% and 77% at 1 year, then dropped to 15% and 22%, respectively after 5years. Twelve patients were treated by artificial urinary sphincter implantation, five by ProACT™ balloons and one by a re-do I-Stop TOMS™. No severe complications were recorded at last follow-up. I-Stop TOMS™ implantation is a safe and effective option in the short-term for mild to moderate PPI management. However, a significant trend to recurrence of leakage has been established after long-term follow-up. If confirmed by further studies, these results may substantially impact patient information before male sling implantation. 4.


Creatine supplementation does not affect clinical health markers in football players.
To study the effects of 8-week creatine monohydrate (CrM) supplementation on blood and urinary clinical health markers in football players. 14 football players were randomly assigned in a double-blinded fashion to Cre (n = 7) or Pla (n = 7) group. The Cre group ingested 15 g/day of CrM for 7 days and 3 g/day for the remaining 49 days, whereas the Pla group ingested maltodextrin following the same protocol. Football-specific training was performed during the study. Total body mass was determined and blood and urine samples were analysed for metabolic, hepatic, renal and muscular function markers, before and after supplementation. A gain of total body mass was observed after CrM intake, but not with placebo. Blood and urinary markers remained within normal reference values. There were no significant changes in renal and hepatic markers after CrM intake. However, total creatine kinase (CK) activity significantly increased, and uric acid level tended to decrease after CrM use. Likewise, serum glucose decreased in the Cre group following supplementation. No significant differences in urine parameters were found in either group after supplementation. 8 weeks of CrM supplementation had no negative effects on blood and urinary clinical health markers in football players. Properties of CrM may, however, be associated with an increase in CK activity, improving the efficiency for ATP resynthesis, a phenomenon indirectly confirmed by the decreasing tendency in uric acid concentration. Furthermore, CrM seems to slightly influence glucoregulation in trained subjects.


Successful experience in bridging patients to heart transplantation with the MicroMed DeBakey ventricular assist device.
Pulsatile left ventricular assist devices are used with increasing frequency to bridge patients with end-stage heart failure to heart transplantation (HTx). Implantation of pulsatile devices is a cumbersome surgical procedure that is associated with major complications, such as bleeding, thromboembolism, and infection. Recently, a continuous axial flow left ventricular assist device (DeBakey ventricular assist device) has been introduced with the goal of reducing the incidence of major complications. We reviewed our experience with 11 patients who received a DeBakey ventricular assist device axial flow pump for bridge to HTx from April 2000 through November 2001. Two patients (18.2%) died of multiple-organ failure while on left ventricular assist device support. Bleeding requiring thoracotomy occurred in 2 patients (18.2%). One patient had a minor neurologic event, and one patient developed left ventricular assist device thrombosis, which was successfully treated without pump exchange. Renal failure developed in 1 patient and hepatic dysfunction in 2 patients. There were no instances of right heart failure. No device, pocket, or drive-line infections occurred. Nine patients (9 of 11, 81.8%) had HTx within 51 +/- 49 days (range, 11 to 141 days) after left ventricular assist device implant. One patient died 29 days after HTx because of acute rejection. The continuous axial flow DeBakey ventricular assist device had reliable features, including a high rate of bridge to HTx. This device had low complication and system failure rates. We consider the DeBakey ventricular assist device a favorable alternative to pulsatile heart assist devices as a bridge to HTx.


Autoantibody selection and production in early human life.
Natural antibodies are autoreactive/polyreactive antibodies believed to be secreted in the absence of xenoantigens. The origin and functional role of this limited and selective autoimmunity are not clear, nor is the specificity and range of autoantigens that drive the development of B cells producing natural antibodies. In this issue of the JCI, Merbl et al. report that in utero, humans generate natural IgM and IgA antibodies that recognize a uniform set of autoantigens (see the related article beginning on page 712), some of which are associated with autoimmune diseases. The authors postulate that this "autoimmunity" at birth favors the emergence of autoimmune diseases in later life. We present a molecular basis for the limited and common repertoire of antibodies produced by fetal B cells, which may be distinct from the abnormalities in B cell development described in patients with autoimmune diseases.


Bacterial Enrichment Cultures Biotransform the Mycotoxin Deoxynivalenol into a Novel Metabolite Toxic to Plant and Porcine Cells.
The mycotoxin deoxynivalenol (DON), produced in wheat, barley and maize by Fusarium graminearum and Fusarium culmorum, is threatening the health of humans and animals. With its worldwide high incidence in food and feed, mitigation strategies are needed to detoxify DON, maintaining the nutritional value and palatability of decontaminated commodities. A promising technique is biological degradation, where microorganisms are used to biotransform mycotoxins into less toxic metabolites. In this study, bacterial enrichment cultures were screened for their DON detoxification potential, where DON and its potential derivatives were monitored. The residual phytotoxicity was determined through a bioassay using the aquatic plant Lemna minor L. Two bacterial enrichment cultures were found to biotransform DON into a still highly toxic metabolite for plants. Furthermore, a cytotoxic effect was observed on the cellular viability of intestinal porcine epithelial cells. Through liquid chromatography high-resolution mass spectrometry analysis, an unknown compound was detected, and tentatively characterized with a molecular weight of 30.0 Da (i.e., CH2O) higher than DON. Metabarcoding of the subsequently enriched bacterial communities revealed a shift towards the genera Sphingopyxis, Pseudoxanthomonas, Ochrobactrum and Pseudarthrobacter. This work describes the discovery of a novel bacterial DON-derived metabolite, toxic to plant and porcine cells.


Tumor necrosis factor-alpha down-regulates human Cu/Zn superoxide dismutase 1 promoter via JNK/AP-1 signaling pathway.
Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells. We herein show that TNF-alpha decreases SOD1 mRNA, protein, and promoter activity in U937 cells. Electrophoretic mobility-shift assays (EMSA) show that TNF-alpha decreased binding of three different complexes. Ectopic Sp1 overexpression markedly increased SOD1-basal promoter activity and partially antagonized the TNF-alpha inhibitory effect. In contrast, ectopic c-Jun overexpression mimics TNF-alpha inhibitory effects and antagonizes Sp1 stimulatory effects. In agreement with these findings, EMSA shows a TNF-alpha-induced increase in AP-1 and a decrease in Sp1 DNA binding. Disruption of the C/EBP site decreases, whereas mutation in the Sp1/Egr-1 site completely abolishes DNA-binding and promoter activity. A JNK inhibitor antagonized the negative effects of TNF-alpha on SOD1 promoter activity, suggesting that JNK signaling through c-Jun protein activation is critical for the TNF-alpha-dependent SOD1 repression. A greater understanding of the mechanisms of TNF-alpha-induced SOD1 repression could facilitate the design and development of novel therapeutic drugs for inflammatory conditions.


[Hemostasis in patients operated on for abdominal hemorrhage. 4. Conception of hemostasis changes].
Studies of haemostasis changes in the dynamics of early post-operational period permitted revealing the tendency to the growth of fibrinogen concentration, decrease in the fibrinogen self-assembling rate, weakening of thrombinemia, disturbances in fibrinogen degradation products (FDP) elimination, increase of inhibitors activity and/or weakening of blood coagulation factors activity, intensification thrombocytes aggregation. Hypercoagulation has been registered under acute haemorrhage and the haemorrhage time exceeding 24 h before the operation, the weakening of hypercoagulation response was observed, notwithstanding the possibility of haemorrhage continuation. The letter is underlined by the changes in the balance between the coagulation factors and inhibitors up to the absence of typical hypercoagulation response to surgical interference.


Metabolic consequences of sex reversal in two lizard species: a test of the like-genotype and like-phenotype hypotheses.
Vertebrate sex is typically determined genetically, but in many ectotherms sex can be determined by genes (genetic sex determination, GSD), temperature (temperature-dependent sex determination, TSD), or interactions between genes and temperature during development. TSD may involve GSD systems with either male or female heterogamety (XX/XY or ZZ/ZW) where temperature overrides chromosomal sex determination to cause a mismatch between genetic sex and phenotypic sex (sex reversal). In these temperature-sensitive lineages, phylogenetic investigations point to recurrent evolutionary shifts between genotypic and temperature-dependent sex determination. These evolutionary transitions in sex determination can occur rapidly if selection favours the reversed sex over the concordant phenotypic sex. To investigate the consequences of sex reversal on offspring phenotypes, we measured two energy-driven traits (metabolism and growth) and 6 month survival in two species of reptile with different patterns of temperature-induced sex reversal. Male sex reversal occurs in Bassiana duperreyi when chromosomal females (female XX) develop male phenotypes (maleSR XX), while female sex reversal occurs in Pogona vitticeps when chromosomal males (male ZZ) develop female phenotypes (femaleSR ZZ). We show metabolism in maleSR XX was like that of male XY; that is, reflective of phenotypic sex and lower than genotypic sex. In contrast, for Pogona vitticeps, femaleSR ZZ metabolism was intermediate between male ZZ and female ZW metabolic rate. For both species, our data indicate that differences in metabolism become more apparent as individuals become larger. Our findings provide some evidence for an energetic advantage from sex reversal in both species but do not exclude energetic processes as a constraint on the distribution of sex reversal in nature.


Inferior vena cava injury during percutaneous vertebroplasty: a rare cause of fatal pulmonary thromboembolism.
Fatal pulmonary thromboembolism (PTE) following percutaneous vertebroplasty is rare in medical practice. Here, we report the case of a 70-year-old woman who suffered from lumbago with lower extremity pain and lameness and for whom lumbar osteoporotic vertebral compression fractures (L4, L5) were seen on MRI examination. Percutaneous vertebroplasty and posterior vertebral lamina fenestration discectomy were performed. One day later, her condition deteriorated after defecation, and she died suddenly. Pulmonary thromboembolus and deep venous thrombosis in the inferior vena cava were the major findings at forensic autopsy. Due to the rather uncommon components of the thromboembolus (chondrocytes, calcium deposits, and collagen fibers), the pulmonary thromboembolism was attributed to deep venous thrombosis in the inferior vena cava, which was injured during percutaneous vertebroplasty. The present study highlights the conclusion that pulmonary thromboembolism is a rare complication of percutaneous vertebroplasty that should attract the attention of clinical physicians and forensic pathologists.


[Outpatient use of topical antimicrobials in Spain associated with other drugs (2005-2007)].
The consumption of antibiotics for systemic use has been well studied. However, data of topical use in our country are an anecdotal reference in the literature. To evaluate the outpatient use of topical antimicrobials in Spain associated with other drugs during the period December 2005 and November 2007. A descriptive quantitative study was conducted between December 1, 2005 to November 30, 2007. The sample amounted to a total of 112 drugs, representing 131 dosage forms. The data on consumption of drugs were sold by the company Intercontinental Marketing Services (IMS), while demographic data were obtained from the municipal census of 2006 and 2007. The study variables were grouped into three categories: those relating to consumption, those on medications and other variables such as geographic location and time period. During the study period the outpatient consumption of topical antimicrobials in Spain was 41.755.951 vials (130.637.368 euros) whose composition included associations between antimicrobials or antimicrobials with other drugs. The average monthly consumption amounted to 1.739.831 vials and 5.443.223 euros. The dermal route of administration was the most dispensed and according to the Anatomical, Therapeutic, Chemical classification system (ATC) and the D07CC subgroup was the most used. The association between tobramycin and dexamethasone ophthalmic suspension as 30% was the drug most used in Spain. The consumption of topical antimicrobials in Spain during the period 2006-2007 increased by 2.36% in the number of vials and 7.28% in economic cost. These antimicrobials were more used in summer. The average cost of a topical antimicrobial was half (3.13 euros) compared to the average cost of a drug (7.89 euros).


Percutaneous cryoablation of hepatic tumors: long-term experience of a large U.S. series.
To report our long-term experience with percutaneous cryotherapy for primary and metastatic liver tumors, including historical perspectives on complications over time and local recurrence rates. Following IRB approval under HIPAA compliance, 342 CT fluoroscopic-guided, percutaneous cryotherapy procedures were performed for 443 masses in 212 outpatients with hepatocellular carcinoma (HCC; N = 36), or metastatic disease (N = 176), grouped as colorectal carcinoma (CRC) and non-CRC metastases. Tumor and ablation sizes were noted in relation to adjacent vasculature. All complications were graded according to standardized criteria. Patients were followed by CT and/or MRI at 1, 3, 6, 12, 18, 24 months and yearly thereafter. Local recurrences were defined as either "procedural" within the ice ablation zone, or "satellite" within 1 cm of the ablation rim to evaluate recurrence patterns. Average tumor diameter of 2.8 cm was treated by average cryoprobe number of 4.5, which produced CT-visible ice ablation zone diameters averaging 5.2 cm. Grade >3 complications were primarily hematologic [N = 20/342; (5.8%)], and appeared related to pre-procedural anemia/thrombocytopenia, carcinoid tumor type, and large ablation volumes. No significant central biliary leak, strictures, or bilomas were noted. At a mean follow-up of 1.8 years, local tumor recurrences were 5.5%, 11.1%, and 9.4% for HCC, CRC, and non-CRC metastases, respectively, consisting mainly of satellite foci. No significant difference was noted for local recurrences near major blood vessels or tumors >3 cm diameter. Percutaneous hepatic cryotherapy is a well-visualized, safe procedure that produces very low local recurrence rates, even for tumors near vasculature and diameters over 3 cm. Cryoablation deserves to be in the armamentarium of percutaneous hepatic ablation, especially with careful patient selection for tumors <4 cm and patients with platelet counts >100,000. Percutaneous hepatic cryoablation represents a highly flexible technique with particular benefits near central biliary structures and/or adjacent crucial structures.


[Two new species of the genus Argyrana (Lepidoptera: Noctuidae)].
The moth genus Argyrana was described by Koehler in 1951. We studied 539 specimens and here redescribe the adults, male and female genitalia. Two new species are reported for Araucania and Aysén (IX Region and XI Region, Chile; the genus was previously known only from Argentina). These moths fly in October, November and February.