Circulating Double-Stranded DNA in Plasma of Hemodialysis Patients and its Association with Iron Stores.
Chronic kidney disease (CKD) is characterized by oxidative stress, and most of the adverse effects of CKD are mediated by iron-catalyzed ROS generation. The DNA, in particular, is more susceptible to attack by ROS than other proteins and membrane lipids. Considering the evidence on the relationship between CKD, iron metabolism, and DNA damage, the purpose of this study was to evaluate cell-free DNA in the plasma of HD patients and its association with iron status biomarkers and kidney function. Measurements of the circulating cell-free DNA in plasma, iron, ferritin, transferrin and other biochemical parameters were performed in 40 chronic hemodialysis (HD) patients and 40 healthy controls. Blood samples were also collected 1 hour before and 1 hour after the HD session to check whether a single HD session would be able to promote an increase in cell-free DNA in the plasma. Cell-free DNA in plasma was significantly increased in HD patients in comparison with healthy controls (p = 0.0017), and significant correlations were observed between cell-free DNA and GFR and ferritin. Our findings showed that a single HD session was not able to promote an increase in cell-free DNA. It was reported that increased ferritin levels and reduced GFR were associated with higher circulating cell-free DNA. The HD patients presented increased ceIl-free DNA. In addition, the increase of ferritin levels and the decrease of GFR were associated with DNA damage. We also observed that a single HD session was not able to promote an increase in cell-free DNA.


Assessment of endocervical and endometrial damage inflicted by embryo transfer trial: a hysteroscopic evaluation.
The aim was to assess the endocervical and endometrial damage inflicted by embryo transfer trial using office hysteroscopy. Seventy-five consecutive infertile women who underwent office hysteroscopy were enrolled. Hysteroscopy was performed immediately after embryo transfer trial. The relationship between clinical perception of easiness of transfer, presence of blood on the catheter, degree of endocervical and endometrial damage was examined. In the difficult transfer group, minor and moderate endocervical lesions were noted in 35% and 24% of the cases, respectively. The respective figures for the easy transfer group were 19% and 3% (P>.05). There was a statistically significant concordance between the perceived difficulty of transfer and degree of endometrial damage (P<0.05). Of interest, in the easy transfer group, 32% of the patients had minor, 3% moderate and 65% no endometrial damage. The respective figures were 42%, 29% and 29% in the difficult transfer group. There was blood on the catheter in 25%, 56% and 71% of the easy, moderate and difficult transfer groups, respectively. There was a statistically significant concordance between the perceived difficulty of embryo transfer and presence of blood on the catheter (P<0.05). These results suggest that clinical perception of difficulty of transfer and the presence of blood on the catheter are directly associated with endometrial disruption.


[Urinary iodine excretion levels in schoolchildren from Quindío, 2006-2007].
Iodine nutritional status is measured by urinary iodine concentration thereby allowing risks involved in such deficiency or increase to be assessed. Studying the frequency of the risk of iodine deficiency disorders, or more than suitable iodine intake in schoolchildren from Quindío. Urinary iodine concentration was measured in a casual urine sample taken from each subject; this study lasted from 2006 to 2007. Median urinary iodine was 272.4 microg/L in the 444 samples analysed. 11.9% of schoolchildren had normal urinary iodine, 28.8% had iodine deficiency and 11.5% of them had a severe deficit, 12.6% moderate deficit and 4.7% slight deficit. 59.3% presented a risk of excessive iodine intake. The range of iodine deficiency in boys was 31% and 26.6% in girls (no significant difference). No significant difference was found with age; however, there was a significant difference between economic levels 1 and 2 (p <0.000). Municipalities in rural areas had 100% iodine deficiency (median um < 100 microg/L) whilst those in the urban area (Armenia, Tebaida and The Caimo) had excessive iodine intake. The population being studied had severe iodine deficiencies (rural) and excessive intake (urban population), suggesting the absence or poor control of an iodization programme and additional exposure to factors causing iodine disorders. A programme is required for monitoring iodine disorders in the school population being studied.


Alzheimer's Abeta40 studied by NMR at low pH reveals that sodium 4,4-dimethyl-4-silapentane-1-sulfonate (DSS) binds and promotes beta-ball oligomerization.
The Alzheimer's Abeta40 peptide forms soluble oligomers that are extremely potent neurotoxins and strongly impede synapses function. In this study the formation and structure of the large, soluble, neurotoxic Abeta40 oligomer called "beta-ball" were characterized by two-dimensional NMR, circular dichroism, fluorescence spectroscopy, hydrogen exchange, and equilibrium sedimentation. In acidic aqueous solution, half the Abeta40 molecules are in the beta-ball state; the remainder are monomeric. The equilibrium between the two states is slow as judged by NMR linewidths and is stable for months. The kinetics of beta-ball formation from monomer are biphasic with tau1 = 7 min and tau2 = 80 min with no transient helix formation. Monomeric Abeta40 is essentially devoid of stable secondary structure, although the central, Leu17-Ala21, and C-terminal, Gly29-Val40, hydrophobic regions show propensity toward adopting extended structure, and residues 22-25 tended to form a turn. We found that sodium 4,4-dimethyl-4-silapentane-1-sulfonate (DSS) binds to the central hydrophobic region of monomeric Abeta40. DSS binds beta-balls more strongly and caused them to double in size. Plausible micelle-like models for the beta-ball structure with and without bound DSS are presented.


Epilepsy in multiple sclerosis: The role of temporal lobe damage.
Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS ( p< 0.05 for all comparisons). Compared to RRMS, RRMS/E showed more severe damage of temporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.


Biohydrogen and biomethane production from food waste using a two-stage dynamic membrane bioreactor (DMBR) system.
This study examined a two-stage dynamic membrane bioreactor (DMBR) system for biohydrogen and biomethane production from food waste (FW) in mesophilic condition. The two-stage DMBR system enabled high-rate H2 and CH4 production from particulate feedstock by enhanced microorganism retention. Chemical energy in FW was recovered up to 79% as renewable energy. The highest average hydrogen production rate of 7.09 ± 0.42 L/L-d was observed at a hydraulic retention time (HRT) of 8 h in the H2-DMBR, while the highest CH4 average production rate of 0.99 ± 0.02 L/L-d was observed at an HRT of 6 d in the CH4-DMBR. The high specific methanogenic activity of 71.7 mL CH4/g VSS-d was maintained at the short HRT, which also contributed to the high MPR. The genus Clostridium was dominant in the H2-DMBR, while bacterial and archaeal populations in the CH4-DMBR were dominated by the class Clostridia and genera Methanobacterium and Methanosaeta, respectively.


PKC-δ isoform plays a crucial role in Tat-TLR4 signalling pathway to activate NF-κB and CXCL8 production.
HIV-1 Tat protein induces the production of CXCL8 chemokine in a TLR4/MD2 and PKC dependent manner. The objective of this study was to understand whether these two pathways were distinct or constituted a single common pathway, and to determine the nature of the PKC isoforms involved and their interrelation with the activation of NF-κB and CXCL8 gene product expression. Here, we show that Tat-induced CXCL8 production is essentially dependent on the activation of PKC delta isoform, as shown a) by the capacity of PKC delta dominant negative (DN), and Rottlerin, a selective PKC delta pharmacological inhibitor, to inhibit Tat-induced CXCL8 production and b) by the ability of the constitutively active (CAT) isoform of PKC delta to induce CXCL8 production in a HEK cell line in the absence of Tat stimulation. The finding that comparable amounts of CXCL8 were produced following stimulation with either Tat protein, PKC-delta CAT transfection, or both, argue for the implication of one common pathway where PKC delta is activated downstream of TLR4 recruitment and leads to the activation of NF-κB. Altogether, our results underline the crucial role of PKC delta isoform in activating gene expression of CXCL8, a cytokine largely implicated in the physiopathology of HIV-1 infection.


Failure to reduce short-term appetite following alcohol is independent of beliefs about the presence of alcohol.
Previously, it has been reported that energy consumed as alcohol prior to lunch does not result in subsequent reductions in voluntary food intake, and in some situations alcohol can increase subsequent appetite. The present study extends these findings by examining the effects of beliefs about alcohol content. Eighteen unrestrained men ate lunch 20 min after a preload of either water, an alcoholic beer or a non-alcoholic beer matched for energy content. Food intake was significantly less following the non-alcoholic beer than after alcohol or water, but when preload energy was included subjects had a higher overall energy intake on the day they consumed alcohol compared with both water and no-alcohol conditions. There were no significant differences in hunger or fullness ratings following the three drinks before or after the test meal, but the specific relationship between rated hunger and intake within the test meal was altered by the drink manipulation. The rate at which hunger decreased, and fullness increased, was slower after alcohol than after water or no-alcohol. The drinks did not alter the pleasantness of the test meal or increase hunger at the start of eating. When contrasted with previous work, these data confirm that alcohol consumed before lunch fails to reduce subsequent food intake, but also suggests that changes in rated appetite are influenced by beliefs about alcohol content.


Getting Past Words: Futility and the Professional Ethics of Life-Sustaining Treatment.
For nearly three decades, clinicians and bioethicists have debated about use of the term futile to describe end-of-life medical interventions that clinicians believe are no longer warranted. In clinical practice, the term is most often invoked when a family of a dying or permanently unconscious patient insists upon such interventions, despite the medical team's belief or recommendation that they be withheld or withdrawn. This essay argues that each of the commonly used terms for these interventions (futile, inappropriate, and nonbeneficial) captures an important, different, and complementary facet of these conflicts in end-of-life medical care. Rather than continuing to debate which term is best, clinicians and bioethicists should direct their attention to the professional ethics of end-of-life care and the clinical and organizational factors that create or contribute to these so-called "futility cases."


Foundation for an evidence-informed algorithm for treating pelvic floor mesh complications: a review.
To address evidence gaps on the management of complications related to mesh in pelvic floor surgery, we created an evidence-based algorithm that includes defining evidence gaps. We utilized the Delphi method within a panel of surgeons treating mesh complications to define a treatment strategy. The first round provided a list of clinically based postulates that informed a review expanding postulates to recommendations and included grading of the quality of evidence. A second round informed the final algorithm. While the quality of the available evidence is low, it provides a framework for planning diagnosis and management of mesh-related complications. Removal of mesh must balance resolution of complications with the risk of removal and recurrence of pelvic floor symptoms.


The Effects of Two Self-Regulation Interventions to Increase Self-Efficacy and Group Exercise Behavior in Fitness Clubs.
Studies on the adoption and maintenance of group exercise behavior are scarce. The objective of this study is to test two self-efficacy based interventions to increase barrier self-efficacy and group exercise behavior. In total 122 participants (Mage 42.02 yr.; SD 12.29; 67% females) were recruited and randomly assigned to one control and two experimental groups. The control group was limited to participate in one virtual group exercise program only (group 1). The first experimental group was able to self-set their activities and participate in multiple group exercise programs (group 2). The second experimental group received an additional monthly coaching protocol to manage self-set goals (group 3). A validated scale for barrier self-efficacy was used, group exercise sessions were measured and drop-out rates were registered. An ANOVA indicated that mean amount of sessions of group 1 and 3, and 2 and 3 differed significantly (p < 0.05) in 12 weeks. Descriptive statistics demonstrate mean group exercise sessions over the total of 12 weeks of 2.74 (SD 4.65) in the control group; 4.75 (SD 6.08) in the first experimental group, and 12.25 (SD 9.07) for the second experimental group. Regression analysis indicated that self-efficacy at 8-weeks explained the highest variance in overall group exercise sessions (R(2) = 0.18; p < 0.05). Overall drop-out rates were 88% in group 1, 78% in group 2 and 48% in group 3. The results showed that group exercise behavior can significantly be improved by a coaching protocol on self-set goals. Future research should address the effectiveness of self-set activities and self-set goals for a longer period of time and in other types of exercise programs. Key pointsApproximately 144 million individuals exercise in fitness clubs worldwide.About 50% participate in at least one group exercise program and 23% participate only in group exercise classes with instructor.Research on attendance and exercise behavior in fitness clubs is limited but there are strong indications that the frequencies are low.This study demonstrates that group exercise behavior in fitness clubs can be improved significantly by a coaching protocol on self-set goals based on tenets of self-efficacy theory.


MicroRNA-101 attenuates pulmonary fibrosis by inhibiting fibroblast proliferation and activation.
Aberrant proliferation and activation of lung fibroblasts contribute to the initiation and progression of idiopathic pulmonary fibrosis (IPF). However, the mechanisms responsible for the proliferation and activation of fibroblasts are not fully understood. The objective of this study was to investigate the role of miR-101 in the proliferation and activation of lung fibroblasts. miR-101 expression was determined in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis. The regulation of miR-101 and cellular signaling was investigated in pulmonary fibroblasts in vitro The role of miR-101 in pulmonary fibrosis in vivo was studied using adenovirus-mediated gene transfer in mice. The expression of miR-101 was down-regulated in fibrotic lungs from patients with IPF and bleomycin-treated mice. The down-regulation of miR-101 occurred via the E26 transformation-specific (ETS) transcription factor. miR-101 suppressed the WNT5a-induced proliferation of lung fibroblasts by inhibiting NFATc2 signaling via targeting Frizzled receptor 4/6 and the TGF-β-induced activation of lung fibroblasts by inhibition of SMAD2/3 signaling via targeting the TGF-β receptor 1. Adenovirus-mediated miR-101 gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that miR-101 is an anti-fibrotic microRNA and a potential therapeutic target for pulmonary fibrosis.


Activation of mirror-neuron system by erotic video clips predicts degree of induced erection: an fMRI study.
Although visually-induced erection is a common occurrence in human male behaviour, the cerebral underpinnings of this response are not well-known. We hypothesized that the magnitude of induced erection would be linearly correlated with the activation of the mirror-neuron system in response to sexually explicit films. When presented with sexual video clips, eight out of ten healthy subjects had an erectile response demonstrated through volumetric penile plethysmography. The level of activation of the left frontal operculum and of the inferior parietal lobules, areas which contain mirror neurons, predicted the magnitude of the erectile response. These results suggest that the response of the mirror-neuron system may not only code for the motor correlates of observed actions, but also for autonomic correlates of these actions.


Use of Mini-anchors and Rehabilitation with 0° Cusp Angle Teeth Complete Denture in Recurrent Condylar Dislocation: Technical Adequacy and Procedure.
To report a case of association between the surgical treatment of temporomandibular dysfunction and rehabilitation with denture total prosthesis (TP) using nonanatomic teeth (cusp 0°) in patients with anterior recurrent dislocation of the temporo-mandibular joint (TMJ) and persistent uncontrolled mandibular movement, showing a technical adaptation and conduct. There are several treatment approaches available for dislocation of the TMJ. The use of condylar mini-anchors for recurrent TMJ dislocation is a valid option and should be considered since it does not alter the joint anatomy. In edentulous patients undergoing TMJ surgical procedures, prosthetic rehabilitation can be seen as a means of treatment preservation. A 73-year-old female patient attended the oral and maxillofacial surgery clinic presenting with joint instability, ligament laxity, and chronic recurrent TMJ dislocations. She had already been through three previous unsuccessful surgical procedures. A treatment plan was done based on the installation of a mini-anchor in the patient's TMJ through the preauricular surgical access. Dislocations were then resolved, but the lack of mandibular control even to a lesser extent after surgery precluded the use of prosthetics even at rest. Thus, it was planned to manufacture two conventional TPs with 0° cusp angle teeth, a clinical protocol shortened to three sessions in an attempt to improve the stability of the prosthesis. The use of an individual mini-anchor is simple and effective, and the use of artificial teeth is well suited to the case. A multidisciplinary intervention (surgery/ prosthesis) is of utmost importance for the resolution and preservation of the treatment of these complex cases.


Molecular phylogeny of parasitic Platyhelminthes based on sequences of partial 28S rDNA D1 and mitochondrial cytochrome c oxidase subunit I.
The phylogenic relationships existing among 14 parasitic Platyhelminthes in the Republic of Korea were investigated via the use of the partial 28S ribosomal DNA (rDNA) D1 region and the partial mitochondrial cytochrome c oxidase subunit 1 (mCOI) DNA sequences. The nucleotide sequences were analyzed by length, G + C %, nucleotide differences and gaps in order to determine the analyzed phylogenic relationships. The phylogenic patterns of the 28S rDNA D1 and mCOI regions were closely related within the same class and order as analyzed by the PAUP 4.0 program, with the exception of a few species. These findings indicate that the 28S rDNA gene sequence is more highly conserved than are the mCOI gene sequences. The 28S rDNA gene may prove useful in studies of the systematics and population genetic structures of parasitic Platyhelminthes.


Investigating Transporter-Mediated Drug-Drug Interactions Using a Physiologically Based Pharmacokinetic Model of Rosuvastatin.
Rosuvastatin is a frequently used probe in transporter-mediated drug-drug interaction (DDI) studies. This report describes the development of a physiologically based pharmacokinetic (PBPK) model of rosuvastatin for prediction of pharmacokinetic (PK) DDIs. The rosuvastatin model predicted the observed single (i.v. and oral) and multiple dose PK profiles, as well as the impact of coadministration with transporter inhibitors. The predicted effects of rifampin and cyclosporine (6.58-fold and 5.07-fold increase in rosuvastatin area under the curve (AUC), respectively) were mediated primarily via inhibition of hepatic organic anion-transporting polypeptide (OATP)1B1 (Inhibition constant (Ki ) ∼1.1 and 0.014 µM, respectively) and OATP1B3 (Ki ∼0.3 and 0.007 µM, respectively), with cyclosporine also inhibiting intestinal breast cancer resistance protein (BCRP; Ki ∼0.07 µM). The predicted effects of gemfibrozil and its metabolite were moderate (1.88-fold increase in rosuvastatin AUC) and mediated primarily via inhibition of hepatic OATP1B1 and renal organic cation transporter 3. This model of rosuvastatin will be useful in prospectively predicting transporter-mediated DDIs with novel pharmaceutical agents in development.


Engineering microbial phenotypes through rewiring of genetic networks.
The ability to program cellular behaviour is a major goal of synthetic biology, with applications in health, agriculture and chemicals production. Despite efforts to build 'orthogonal' systems, interactions between engineered genetic circuits and the endogenous regulatory network of a host cell can have a significant impact on desired functionality. We have developed a strategy to rewire the endogenous cellular regulatory network of yeast to enhance compatibility with synthetic protein and metabolite production. We found that introducing novel connections in the cellular regulatory network enabled us to increase the production of heterologous proteins and metabolites. This strategy is demonstrated in yeast strains that show significantly enhanced heterologous protein expression and higher titers of terpenoid production. Specifically, we found that the addition of transcriptional regulation between free radical induced signalling and nitrogen regulation provided robust improvement of protein production. Assessment of rewired networks revealed the importance of key topological features such as high betweenness centrality. The generation of rewired transcriptional networks, selection for specific phenotypes, and analysis of resulting library members is a powerful tool for engineering cellular behavior and may enable improved integration of heterologous protein and metabolite pathways.


Fully Coupled Two-Fluid Dynamics in Superfluid ^{4}He: Anomalous Anisotropic Velocity Fluctuations in Counterflow.
We investigate the thermal counterflow of the superfluid ^{4}He by numerically simulating three-dimensional fully coupled dynamics of the two fluids, namely quantized vortices and a normal fluid. We analyze the velocity fluctuations of the laminar normal fluid arising from the mutual friction with the quantum turbulence of the superfluid component. The streamwise fluctuations exhibit higher intensity and longer-range autocorrelation, as compared to transverse ones. The anomalous fluctuations are consistent with visualization experiments [Mastracci et al., Phys. Rev. Fluids 4, 083305 (2019)PLFHBR2469-990X10.1103/PhysRevFluids.4.083305], and our results confirm their analysis with simple models on the anisotropic fluctuations. This success validates the model of the fully coupled dynamics and paves the way for solving some outstanding problems in this two-fluid system.


Sequential occurrence of different subtypes of nonpuerperal mastitis in contralateral breasts: a report of two cases.
Nonpuerperal mastitis (NPM) is a nonspecific chronic inflammation in the breast. The two most common pathologic subtypes are idiopathic granulomatous mastitis (IGM) and plasma cell mastitis (PCM). The cause of NPM is unknown, and the recurrence rate is high; however, the sequential development of two different pathologic subtypes of NPM in contralateral breasts of the same patient is rare. Two women who were in their 30 s and with a history of childbearing had an inflammatory mass in one breast, which was identified as PCM by core needle biopsy. However, 1 year after treatment, IGM occurred in the contralateral breast. Histopathologic results after the surgery confirmed both diagnoses. New-onset PCM in both patients was successfully treated with local extended surgical resection and antibiotics combined with incision and drainage. The IGM that developed in the contralateral breast after 1 year was treated with local extended surgical resection and oral steroids. No signs of NPM recurrence were observed in either breast after a follow-up period of more than 1 year. Because recurrence after NPM treatment often occurs in the affected breast, the contralateral breast, which does not often exhibit morbidity factors, is often ignored during treatment follow-up. However, our cases suggest that patients with the occurrence of NPM in one breast should undergo long-term follow-up of the contralateral breast by close monitoring. NPM recurrence should also be considered when there is pain, redness, and swelling in the contralateral breast.


Fabrication of an ionic-liquid-based polymer monolithic column and its application in the fractionation of proteins from complex biosamples.
An ionic-liquid-based polymer monolithic column was synthesized by free radical polymerization within the confines of a stainless-steel column (50 mm × 4.6 mm id). In the processes, ionic liquid and stearyl methacrylate were used as dual monomers, ethylene glycol dimethacrylate as the cross-linking agent, and polyethylene glycol 200 and isopropanol as co-porogens. Effects of the prepolymerization solution components on the properties of the resulting monoliths were studied in detail. Scanning electron microscopy, nitrogen adsorption-desorption measurements, and mercury intrusion porosimetry were used to investigate the morphology and pore size distribution of the prepared monoliths, which showed that the homemade ionic-liquid-based monolith column possessed a relatively uniform macropore structure with a total macropore specific surface area of 44.72 m2 /g. Compared to a non-ionic-liquid-based monolith prepared under the same conditions, the ionic-liquid-based monolith exhibited excellent selectivity and high performance for separating proteins from complex biosamples, such as egg white, snailase, bovine serum albumin digest solution, human plasma, etc., indicating promising applications in the fractionation and analysis of proteins from the complex biosamples in proteomics research.


Inside the black box: measuring addiction treatment services and their relation to outcomes.
The adoption of performance-based management has been under consideration by addiction treatment funding agencies, and, recently, many state and county agencies have developed performance-based measurement/management systems in an attempt to improve their treatment system. This article describes one such effort in Los Angeles County, California. The Performance-Based Pilot Project linked treatment encounters (counseling sessions, drug testing, case management, and methadone dosing) with client outcomes (abstinence or reduced drug use at discharge) and longer lengths of stay in treatment. Eleven outpatient counseling programs and three narcotic treatment programs participated in the nine-month project. Results indicated that for both outpatient counseling and narcotic treatment programs, more sessions attended in the first 30 days was associated with better client outcomes and longer lengths of stay. Furthermore, in outpatient counseling programs, more group sessions during the first 30 days predicted abstinence or greater reductions in primary drug use; in narcotic treatment programs, more doses received during the first 30 days was correlated to longer treatment retention. This research implies that increasing the availability of counseling sessions for a client's first 30 days and engaging clients early is a promising area for program efforts to improve treatment outcomes and program performance.


Effect of a microwave coagulator on implanted liver neoplasms in rats.
An experimental study was conducted to determine the applicability of a microwave (MW) source for coagulation and dissection of metastatic tumour and liver parenchyma. Twenty PVG rats were studied after implantation of MC28 tumour cells into the liver. Eleven days later they underwent sham laparotomy (control) MW coagulation of the tumour deposit, local resection of the tumour deposit with 2 mm clearance or resection of the tumour with MW coagulation of the resection zone. The control animals all died with blood-stained ascites and heavy tumour burden in the liver. After MW coagulation, tumours disappeared in all but one rat. Local resection also led to tumour clearance in 4 of 5 rats. MW coagulation of the resection zone allowed rapid bloodless resection, and no tumour recurrence was observed after 40-89 days. We conclude that MW coagulation is a potentially useful tool for ablation of hepatic metastasis and as an adjunct to hepatic resection.


Twelve hours of gastric ventilation: a recipe for disaster (a suggested remedy).
A forty-three-day-old infant was intubated by the Neonatal Intensive Care Unit (NICU) staff. A nasogastric tube was in place for the duration. The patient's vital signs remained stable during 12 h of positive pressure ventilation. A Broviac catheter placement was scheduled in the NICU. The position of the tracheal tube (TT) was not verified prior to induction of anaesthesia. After the induction, the patient's condition deteriorated. The TT was found to be positioned within the oesophagus. A near catastrophe was successfully averted by discovering the malpositioned TT and replacing it with a properly positioned TT. We believe that had we clamped the existing nasogastric tube preoperatively, a noticeable abdominal distention would have occurred alerting us to a malpositioned TT. We suggest that clamping a preexisting nasogastric tube may have merit to alert one to a malpositioned TT.


[The Rockefeller Foundation, the Carlsberg Foundation and Danish medical biology in the interwar years. Effects on research and education throughout the 20th century].
Three large scientific institutes were built in Copenhagen, Denmark, between 1928 and 1938 supported by the Rockefeller Foundation in New York. The three institutes were: the Rockefeller Institute of Copenhagen, Juliane Mariesvej, the Biological Institute of the Carlsberg Foundation, and the Institute of Human Genetics, both on Tagensvej (The Carlsberg Foundation in Copenhagen participated in the financing of the two first ones.) In the same period the Rockefeller Foundation supported the construction of a cyclotron at Niels Bohr's Institute of Theoretical Physics. These institutes in Copenhagen sent many co-workers both to the Rockefeller University in New York and to other places in the world for further education supported by stipends from the Rockefeller Foundation. The scientific nucleus around which these activities crystallized included: the physiologist (and Nobel Prize winner) Aug. Krogh, the physicist (and Nobel Prize winner) Niels Bohr, the chemist S.P.L. Sorensen, the geneticist W. Johannsen, the plant physiologist Peter Boysen Jensen, and the cell culturist Albert Fischer. The international co-operation between the two foundations began early in the 20th century and it can be traced in Danish medical/biological science through the rest of that century.


Discrepancies Between Planned and Actual Operating Room Turnaround Times at a Large Rural Hospital in Germany.
While several factors have been shown to influence operating room (OR) turnaround times, few comparisons of planned and actual OR turnaround times have been performed. This study aimed to compare planned and actual OR turnaround times at a large rural hospital in Northern Germany. This retrospective study examined the OR turnaround data of 875 elective surgery cases scheduled at the Marienhospital, Vechta, Germany, between July and October 2014. The frequency distributions of planned and actual OR turnaround times were compared and correlations between turnaround times and various factors were established, including the time of day of the procedure, patient age and the planned duration of the surgery. There was a significant difference between mean planned and actual OR turnaround times (0.32 versus 0.64 hours; P <0.001). In addition, significant correlations were noted between actual OR turnaround times and the time of day of the surgery, patient age, actual duration of the procedure and staffing changes affecting the surgeon or the medical specialty of the surgery (P <0.001 each). The quotient of actual/planned OR turnaround times ranged from 1.733-3.000. Significant discrepancies between planned and actual OR turnaround times were noted during the study period. Such findings may be potentially used in future studies to establish a tool to improve OR planning, measure OR management performance and enable benchmarking.


The relevance of shear, sedimentation and diffusion during spin freezing, as potential first step of a continuous freeze-drying process for unit doses.
Recently, a continuous freeze-drying process for the production of unit doses was presented and evaluated. In this concept, the freezing step is modified compared to traditional batch freeze-drying, as glass vials filled with a liquid formulation, are rotated around their longitudinal axis while cooled and frozen with a cold, sterile and inert gas (i.e. spin freezing). Finally, a thin frozen product layer spread over the entire vial wall is achieved. The aim of this paper is twofold: firstly, the relation between the rotation velocity and the relative difference between top and bottom of the frozen product layer thickness was determined for different vial types. Secondly, the impact of shear and centrifugal forces generated during spinning was examined, to find out whether they might cause pharmaceutical instability and sedimentation, respectively. Mechanistic and experimental evaluation showed that shear has no effect on proteins. Calculations showed that the sedimentation and diffusion velocity is too low to cause inhomogeneity in the product layer. In addition, Global Sensitivity Analysis (GSA) and Uncertainty Analysis (UA) were performed in order to account for the uncertainty of the used mechanistic model.


Inflammatory potential of diet and risk of oral and pharyngeal cancer in a large case-control study from Italy.
Diet and inflammation have been suggested to be important risk factors for oral and pharyngeal cancer. We examined the association between dietary inflammatory index (DII™) and oral and pharyngeal cancer in a large case-control study conducted between 1992 and 2009 in Italy. This study included 946 cases with incident, histologically confirmed oral and pharyngeal cancer, and 2,492 controls hospitalized for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed by a valid 78-item food frequency questionnaire and was adjusted for nonalcohol energy intake using the residual approach (E-DII™). Logistic regression models were used to estimate odds ratios (ORs), and 95% confidence intervals (CIs), adjusted for age, sex, non-alcohol energy intake, study center, year of interview, education, body mass index, tobacco smoking, and alcohol drinking. Subjects with higher DII scores (i.e., with a more pro-inflammatory diet) had a higher risk of oral and pharyngeal cancer, the OR being 1.80 (95% CI 1.36-2.38) for the highest versus the lowest DII quartile and 1.17 (95% CI 1.10-1.25) for a one-unit increase (8% of the DII range). When stratified by selected covariates, a stronger association was observed among women (ORquartile4 v.1 3.30, 95% CI 1.95-5.57). We also observed a stronger association for oral cancers and a strong combined effect of higher DII score and tobacco smoking or alcohol consumption on oral and pharyngeal cancer. These results indicate that the pro-inflammatory potential of the diet, as shown by higher DII scores, is associated with higher odds of oral and pharyngeal cancer.


Quality control for DNA contamination in laboratories using PCR-based class II HLA typing methods.
Quality control (QC) in laboratories performing molecular histocompatibility class II typing often includes a polymerase chain reaction (PCR) approach for monitoring DNA contamination. An oligonucleotide primer set was designed, (RBQBf/RBQBr), which is specific for nonpolymorphic regions of the DR-B, DQ-B, and DP-B consensus sequences with an expected PCR product size of 81 bp. RBQBf/RBQBr detected genomic DNA from reference cell lines LWAGS and BM21 (50 to 100 picograms) as well as DR-B, DP-B, and DQ-B amplicon (1 copy). Additionally, RBQBf/RBQBr detected SSP products from routine DR-B and DQ-B typings. Validation studies employing controlled DNA contamination of laboratory surfaces revealed that increasing amounts of wipe test samples (5% to 20% v/v) were inhibitory to the wipe test PCR, whereas lower amounts (1% to 2%), or alternatively, a diluted wipe test sample, increased the sensitivity of the test and optimized the results. Collectively, this study describes a primer set, RBQBf/RBQBr, which detects both genomic DNA and DR-B, DQ-B, or DP-B amplicon and furthermore illustrates the necessity of routine testing for potential inhibitory factors that may be introduced into the wipe test PCR.


A diet rich in fat and poor in dietary fiber increases the in vitro formation of reactive oxygen species in human feces.
Production of reactive oxygen species in the lumen of the colon, a process that is influenced by nutritional factors, may be important in the etiology of colorectal cancer. Because research on humans in support of this hypothesis is lacking, the objective of this study was to measure the effect of different dietary compositions on the in vitro oxygen radical production in human feces. Over a period of 12 d, seven healthy subjects received a diet rich in fat (50%) and meat and poor in dietary fiber. After a period of 1 wk, they received a vegetarian diet poor in fat (20%) and rich in dietary fiber. At the end of each study period, feces were collected and analyzed for in vitro oxygen radical production with dimethylsulfoxide as the free radical scavenger. The mean hydroxyl radical production was 13 times greater in feces of subjects when they consumed the diet rich in fat and poor in dietary fiber [52.7 +/- 29.5 micromol/(g feces x h)] than when they consumed the diet poor in fat and rich in dietary fiber [3.9 +/- 3.9 micromol/(g feces x h); P < 0.05]. This difference was associated with a 42% higher fecal iron concentration when they consumed the first diet (7.0 +/- 19.2 micromol/g feces) than when they consumed the second (4.9 +/- 1.9 micromol/g feces; P < 0.05). The results of this study confirm that diets high in fat and meat and low in fiber markedly increase the potential for hydroxyl radical formation in the feces, which in turn may contribute to an enhanced risk of colorectal cancer.


Caregiver-child interactive behaviours: a clinical procedure for the development of spoken language in hearing-impaired children.
Much recent research emphasises the importance of pre-verbal communicative behaviour in the language development of children. A child normally becomes a competent user of spoken language through communicative interaction with caregivers in the course of everyday activities and play. When acquisition of spoken language is problematic due to hearing loss, the need to restore and/or maintain the integrity of the caregiver-child interactions is acute. However, relatively few attempts have been made to organise our knowledge of pre-verbal behaviour so that it can be used in developing spoken language in hearing-impaired children. This paper presents a clinical procedure for analysing caregiver-child interactive behaviours, which was derived from language acquisition research and literature. The procedure is intended for use by teachers/clinicians with hearing-impaired children prior to the use of conventional words in connected sentences. A videotape analysis is developed to meet two clinical aims. The first aim is to identify systematically those elements of the interaction which promote the child's communicative development, as well as those which are counterproductive to it. The second aim is to use this information to facilitate communication between caregiver and hearing-impaired child. Illustrative examples from analyses of caregiver-child dyads are provided to demonstrate the clinically useful information which results.


A systematic review of interventions and outcomes in lung cancer metastases to the spine.
Seventy percent of cancer patients will have metastatic bone disease, most commonly in the vertebra. Prognosis of metastatic lung cancer is poor and treatment is mostly palliative. To-date, there is no systematic review on the ideal treatment for lung cancer with spinal metastases in regards to mortality. Literature searches were performed based on PRISMA guidelines for systematic review. Thirty-nine studies comprising 1925 patients treated for spinal metastases of lung cancer met inclusion criteria. All analyses were performed using SAS and SPSS. Data were analyzed for meaningful comparisons of baseline patient characteristics, primary cancer type, metastatic lesion characteristics, treatment modality, and clinical and radiologic outcomes. Significantly greater mean survival length was seen in the non-surgical group (8.5 months, SD 6.6, SEM 0.17) compared to the surgical group (7.5 months, SD 4.5, SEM 0.25; p = 0.013). There was no statistically significant survival difference between different types of primary lung cancer: NSCLC (8.3 months, SD 13.8, SEM 0.91) and SCLC (7.0 months, SD 4.6, SEM 0.46; p = 0.36). Number of vertebral levels involved per lesion also did not exhibit significant difference: single lesion (11.3 months, SD 6.8, SEM 2.2) and multiple lesions (13.8 months, SD 15.7, SEM 3.6; p = 0.64). For patients with symptomatic spinal metastases from lung cancer, non-operative approaches experience significantly better survival outcomes (p = 0.013). Future clinical studies are needed to determine the best treatment algorithm to help maximize outcomes and minimize mortality in metastatic lung cancer.


A comparison of tests for nitrate reduction.
504 strains of different bacteria have been tested for nitrate reduction by a conventional method and two microtests. A quick microtest for nitrate reduction is suggested allowing to read results after 1 hr cultivation. Nitrate reduction is a valuable test particularly for the species differentiation of the genera Bacillus, Micrococcus, Pseudomonas, Alcalignes, Moraxella, and other ones.


S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S).
S-adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) are proapoptotic in HepG2 cells. In microarray studies, we found SAMe treatment induced Bcl-x expression. Bcl-x is alternatively spliced to produce two distinct mRNAs and proteins, Bcl-x(L) and Bcl-x(S). Bcl-x(L) is antiapoptotic, while Bcl-x(S) is proapoptotic. In this study we showed that SAMe and MTA selectively induced Bcl-x(S) in a time- and dose-dependent manner in HepG2 cells. There are three transcription start sites in the human Bcl-x gene which yield only Bcl-x(L) in control HepG2 cells. SAMe and MTA treatment did not affect promoter usage, but while one promoter yielded only Bcl-x(L), the other two yielded both Bcl-x(L) and Bcl-x(S), with Bcl-x(S) as the predominant messenger RNA (mRNA) species. Trichostatin A, 3-deaza-adenosine, cycloleucine, and okadaic acid had no effect on Bcl-x(S) induction by SAMe or MTA. Calyculin A and tautomycin, on the other hand, blocked SAMe and MTA-mediated Bcl-x(S) induction and apoptosis in a dose-dependent manner. SAMe and MTA increased protein phosphatase 1 (PP1) catalytic subunit mRNA and protein levels and dephosphorylation of serine-arginine proteins, with the latter blocked by calyculin A. The effects of SAMe and MTA on Bcl-x(S), PP1 expression, and apoptosis were also seen in 293 cells, but not in primary hepatocytes. Induction of Bcl-x(S) by ceramide in HepG2 cells also resulted in apoptosis. In conclusion, we have uncovered a highly novel action of SAMe and MTA, namely the ability to affect the cellular phosphorylation state and alternative splicing of genes, in this case resulting in the induction of Bcl-x(S) leading to apoptosis.


The early history of neurosurgery in Brazil.
This article describes the professional lives of the founders of neurological surgery in Brazil as well as the Brazilian Society of Neurosurgery. The pioneers were Augusto Brandão Filho, the first general surgeon to perform brain surgery in Brazil, and José Ribe Portugal and Elyseu Paglioli, the founders of the first two neurosurgery schools in Brazil. The Brazilian Society of Neurosurgery was founded in Brussels, Belgium, on July 26, 1957, during the First International Congress of Neurological Surgery, at the initiative of José Ribe Portugal and José Geraldo Albernaz.


Recurrent spontaneous subcutaneous emphysema in a patient with rheumatoid arthritis.
Pulmonary air leak syndromes are extremely rare complications of systemic autoimmune connective tissue diseases and the occurrence of spontaneous subcutaneous emphysema (SSE) from pulmonary leak in the absence of pneumothorax or pneumomediastinum is even rarer. We report a case of recurrent SSE in a patient with rheumatoid arthritis and interstitial lung disease. The SSE was managed conservatively each time and it resorbed over several days. There has been no previous documented report of SSE in the absence of pneumomediastinum, pneumothorax or pulmonary nodules in a patient with RA.


Wnt/β-catenin signaling is required for distraction osteogenesis in rats.
The Wnt signaling pathway plays crucial roles in embryonic skeletal development and postnatal bone regeneration. However, mechanisms of Wnt signaling functioning in distraction osteogenesis (DO) haven't been well characterized. We established a DO model using Sprague-Dawley rat tibia. And a Wnt signaling blocking agent, recombinant rat Dickkopf-related protein 1 (rrDkk1), was locally applied in the distracted gap to study the role of Wnt signaling during DO process. Animals in the experimental group received rrDkk1 injections (dose = 25 μg/kg) once daily during distraction period and every third day during consolidation stage (n = 48). Animals in the control group received saline under the same injection strategy (n = 48). Animals at different time points during DO process (1, 3, 6, 12 days after distraction, 10 days and 6 weeks after consolidation) were killed and tissues in the distraction region were harvested for radiography, dual energy X-ray absorptiometry, micro-computed tomography (micro-CT), and histological analyses. Most Wnt ligands, cofactors, receptors, and antagonists were widely expressed in the distraction callus and were significantly upregulated during DO process. After rrDkk1 administration, the majority of these factors were downregulated at the mRNA level, except sFRP and GSK-3β. At the protein level, both β-catenin and Lef-1 were also suppressed by rrDkk1. In the long term, restricted bone healing was observed in the distracted callus in the rrDkk1 injection group. These findings were confirmed by histological and micro-CT analyses. Our findings suggest that Wnt signaling participates in the process of DO, and clinical therapeutic approaches of DO may do well to avoid Wnt pathway suppression.


Alcohol drinking and mammary cancer: Pathogenesis and potential dietary preventive alternatives.
Alcohol consumption is associated with an increased risk of breast cancer, increasing linearly even with a moderate consumption and irrespectively of the type of alcoholic beverage. It shows no dependency from other risk factors like menopausal status, oral contraceptives, hormone replacement therapy, or genetic history of breast cancer. The precise mechanism for the effect of drinking alcohol in mammary cancer promotion is still far from being established. Studies by our laboratory suggest that acetaldehyde produced in situ and accumulated in mammary tissue because of poor detoxicating mechanisms might play a role in mutational and promotional events. Additional studies indicated the production of reactive oxygen species accompanied of decreases in vitamin E and GSH contents and of glutathione transferase activity. The resulting oxidative stress might also play a relevant role in several stages of the carcinogenic process. There are reported in literature studies showing that plasmatic levels of estrogens significantly increased after alcohol drinking and that the breast cancer risk is higher in receptor ER-positive individuals. Estrogens are known that they may produce breast cancer by actions on ER and also as chemical carcinogens, as a consequence of their oxidation leading to reactive metabolites. In this review we introduce our working hypothesis integrating the acetaldehyde and the oxidative stress effects with those involving increased estrogen levels. We also analyze potential preventive actions that might be accessible. There remains the fact that alcohol drinking is just one of the avoidable causes of breast cancer and that, at present, the suggested acceptable dose for prevention of this risk is of one drink per day.


Relationship of fluorescence and thermal emission from isolated thylakoids under light stress conditions.
Simultaneous measurements of fluorescence and thermal emission have been made by a combined fluorescence and photoacoustic techniques on isolated thylakoids pretreated by a prolonged illumination of saturating light. The traces of the signals are used to calculate four characteristic parameters, energy storage, half-saturation intensity, number of photons to close reaction center, and a constant for quasi-equlibria between (re)oxidized and reduced quinone acceptors. These parameters are used to study the response of photosynthetic apparatus functioning under photoinhibition stress. The defense mechanism seems to possess an efficient cooperativity of reaction centers under stress conditions.


The Biology of Chronic Pain and Its Implications for Pain Neuroscience Education: State of the Art.
Pain is an individualized experience for the person suffering from chronic pain. Significant strides have been made in the last few decades in understanding various biological changes that coincide with chronic pain. This state-of-the-art overview looks at the current evidence related to the biology of chronic pain and the implications these findings have on the delivery of pain neuroscience education (PNE). The paper summarizes the various (epi)genetic, neural, endocrine, and immune factors discovered and explored in the scientific literature concerning chronic pain. Each of these biological factors has various implications for the content and delivery of PNE. We discuss the future directions these biological factors have for the clinical implementation of PNE by linking the importance of behavior change, optimizing the learning environment, and using an individualized multimodal treatment approach with PNE. In addition, future directions for research of PNE based on these biological factors are provided with importance placed on individualized patient-centered care and how PNE can be used with traditional modes of care and growing trends with other care methods. PNE was originally and continues to be rooted in understanding chronic pain biology and how that understanding can improve patient care and outcomes.


Glomus tympanicum chemodectomas: radiographic and clinical characteristics.
Glomus tympanicum chemodectomas are benign neoplasms that develop from normal glomus bodies located along the Jacobson (tympanic) nerve in the middle ear. The medical charts and radiographic studies of 55 patients with these tumors were reviewed. Women outnumbered men in a ratio of 3.5:1, and the patients' average age when they initially reported symptoms was 52 years. Tinnitus, ear pulsations, and diminished hearing were the most frequent symptoms. No patient had a second chemodectoma, and none of seven patients who were tested had elevated neuroendocrine compounds. Review of the radiographic examinations showed that direct coronal, thin-section computed tomography (CT) was the most sensitive means of demonstrating glomus tympanicum chemodectomas. Magnification angiography was also a sensitive diagnostic study, typically depicting a trapezoidal, hypervascular, middle-ear mass that appeared initially in the middle-to-late arterial phase and quickly disappeared in the venous phase. Differentiation from an aberrant internal carotid artery is critical to prevent arterial biopsy.


Loss of KLF14 triggers centrosome amplification and tumorigenesis.
Centrosome amplification is frequent in cancer, but the underlying mechanisms remain unclear. Here we report that disruption of the Kruppel-like factor 14 (KLF14) gene in mice causes centrosome amplification, aneuploidy and spontaneous tumorigenesis. Molecularly, KLF14 functions as a transcriptional repressor of Plk4, a polo-like kinase whose overexpression induces centrosome overduplication. Transient knockdown of KLF14 is sufficient to induce Plk4-directed centrosome amplification. Clinically, KLF14 transcription is significantly downregulated, whereas Plk4 transcription is upregulated in multiple types of cancers, and there exists an inverse correlation between KLF14 and Plk4 protein expression in human breast and colon cancers. Moreover, KLF14 depletion promotes AOM/DSS-induced colon tumorigenesis. Our findings reveal that KLF14 reduction serves as a mechanism leading to centrosome amplification and tumorigenesis. On the other hand, forced expression of KLF14 leads to mitotic catastrophe. Collectively, our findings identify KLF14 as a tumour suppressor and highlight its potential as biomarker and therapeutic target for cancer.


T-cell malignancies with mature phenotypes: altered cell cycle regulation by HLA class I molecules.
Soluble anti-HLA class I monoclonal antibodies (MoAbs) modulate normal T-lymphocyte proliferation induced via the CD3/Ti and the CD2 pathway, but do not induce proliferation of normal T lymphocytes in the absence of additional mitogenic stimuli. In this report, we show that anti-HLA class I MoAbs induce DNA synthesis in peripheral blood mononuclear cells from a patient with a CD4+CD8+T-prolymphocytic leukemia (T-PLL) and from a patient with a CD4-CD8+ T-chronic lymphocytic leukemia (T-CLL), in the absence of detectable additional mitogenic stimuli. Proliferation of leukemic T cells is induced by both whole Igs and Fab' fragments of anti-HLA class I MoAbs, arguing in favor of their direct interactions with the proliferating cells as the mechanism underlying the mitogenic effect. This interpretation is also supported by the ability of anti-HLA class I MoAbs to induce proliferation of leukemic T-cell preparations, depleted of accessory cells. DNA synthesis in T-CLL and T-PLL cells is preceded by expression of G1-specific messenger RNAs, ie. c-myc, 2F1, Tac, and interferon-gamma, in activated cells. Cell proliferation is inhibited by the protein kinase C inhibitor H7, indicating that activation of this enzyme is required for the mitogenic effect of anti-HLA class I MoAbs. The latter inhibit the proliferation of T-CLL cells as well as that of normal T cells stimulated with anti-CD3 MoAbs and enhance that of both types of cells stimulated with anti-CD2 MoAbs. In addition, anti-HLA class I MoAb Q6/64 in combination with anti-CD2 MoAb 9.6 or MoAb 9-1 induces proliferation of leukemic T cells to a greater extent than the individual MoAbs, but is not mitogenic for normal T cells. Anti-HLA class I MoAbs restore the cytolytic activity of T-CLL cells that is lost after 5 days of incubation of control medium, suggesting that HLA class I antigens may mediate a signal contributing to the activation state. The present results indicate that leukemic T-cell proliferation can be triggered via HLA class I molecules and suggest a potential role for these antigens in the in vivo growth of malignant clones.


The marital perceptions of elderly persons living or having a spouse living in a long-term care institution in Canada.
The focus of this study is on the way that older married persons living, or having a spouse living, in a long-term care institution perceive their marriages following relocation. A qualitative analysis of 161 interviews was conducted. For noninstitutionalized spouses (n = 74), four themes emerged from the data--"marriage as a memory," the "illusory marriage," the "changed marriage," and the "continuing marriage." For institutionalized spouses (n = 87), three themes emerged, including the "happy marriage," the "detached marriage," and the "altered marriage." Relocation did not appear to have a direct impact on the way respondents perceived their marriages. Continuity theory was helpful in understanding these marital perceptions.


ABO hemolytic disease in Puerto Rico and North Carolina.
A prospective study was carried out at the University of Puerto Rico Hospital (UPRH) and at the North Carolina Baptist Hospital (NCBH) in order to establish the incidence of ABO hemolytic disease (ABO HD) in the two populations and to determine the relationship of intestinal parasitic infection of the mother to ABO HD in the infant. The incidence of ABO HD among UPRH at risk pregnancies (type O mother with type A or B infant) was 28.3% or 1 in 3.5 as compared with 18.4% or 1 in 5.4 of NCBH at risk pregnancies (P less than .05). Indirect Coombs' tests in cord sera, representing the passive transfer from mother to fetus of antibodies directed toward antigens on the infants' erythrocytes, were positive in 58.8% of UPRH at risk infants as opposed to 40.4% of NCBH at risk infants (P less than .001). Maternal isohemagglutinin titers at term were higher in type O UPRH mothers than in type O NCBH mothers (P less than .01). A relationship between helminth parasitic infection of the mother and ABO HD in the infant was suspected but not proved.


Improved graft prognosis by treatment of steroid resistant rejections with ATG and plasmapheresis.
Conventional therapy of acute rejection is almost exclusively based on increased steroid dosage, however, a considerable number of grafts undergo irreversible steroid resistant rejection (SRR). We investigated in a prospective study the effects of antithymocyte globulin (ATG) and plasmafiltration (PF) in cases of SRR. Acute interstitial rejections were treated with ATG, acute vascular rejections with PF. Thirty-nine of 42 (93%) cases of SRR were reversed by these forms of therapy. In 68 recipients of first cadaveric renal allografts actuarial one year graft survival has improved to 88 (+/- 5) per cent since the introduction of ATG and PF for SRR. Severe side effects or increased mortality were not observed, none of the patients with either form of therapy died. Thus ATG and PF are valuable adjuncts in the treatment of SRR.


[Social workers and the confidentiality in pediatric emergencies].
Social workers are subject to professional secrecy as well as other actors involved in prevention and healthcare. In paediatric emergencies in particular, it is a key partner for the medical and healthcare team. If family support requires information sharing, it is restricted to what is necessary for treatment.


Transmission of spinach downy mildew via seed and infested leaf debris.
Spinach downy mildew, caused by the obligate oomycete pathogen Peronospora effusa, is a worldwide constraint on spinach production. The role of airborne sporangia in the disease cycle of P. effusa is well established, but the role of the sexual oospores in the epidemiology of P. effusa is less clear and has been a major challenge to examine experimentally. To evaluate seed transmission of spinach downy mildew via oospores in this study, isolated glass chambers were employed in two independent experiments to grow out oospore-infested spinach seed and non-infested seeds mixed with oospore-infested crop debris. Downy mildew diseased spinach plants were observed 37 and 34 days after planting in the two isolator experiments, respectively, in the chambers that contained one of two oospore-infested seed lots or seeds coated with oospore-infested leaves. Spinach plants in isolated glass chambers initiated from seeds without oospores did not show downy mildew symptoms. Similar findings were obtained using the same seed lot samples in a third experiment conducted in a growth chamber. In direct grow out tests to examine oospore infection on seedlings performed in a containment greenhouse with oospore-infested seed of two different cultivars, characteristic Peronospora sporangiophores were observed growing from a seedling of each cultivar. The frequency of seedlings developing symptoms from 82 of these oospore-infested seed indicated that approximately 2.4 % of seedlings from infested seed developed symptoms and 0.55% of seedlings from total seeds assayed developed symptoms. The results provide evidence that oospores can serve as a source of inoculum for downy mildew and further evidence of direct seed transmission of the downy mildew pathogen to seedlings in spinach via seedborne oospores.


Susceptibility of Hop Crown Buds to Powdery Mildew and its Relation to Perennation of Podosphaera macularis.
In the Pacific Northwestern United States, the hop powdery mildew fungus, Podosphaera macularis, survives overwintering periods in association with living host tissue because the ascigerious stage of the pathogen is not known to occur in this region. Field experiments were conducted over a 5-year period to describe the overwintering process associated with crown bud infection and persistence of P. macularis. Surface crown buds increased in abundance and size beginning in early July and continuing until mid-September. Buds of varying sizes remained susceptible to powdery mildew until late September to early October in each of 3 years of experiments, with susceptibility decreasing substantially thereafter. Potted plants were inoculated sequentially during early summer to autumn, then evaluated in the following year for development of shoots colonized by the powdery mildew fungus (termed flag shoots) due to bud perennation. Emergence of flag shoots was asynchronous and associated with shoot emergence and elongation. Flag shoots emerged over a protracted period from late February to early June, year dependent. In all 4 years of experiments, some infected buds broke and produced flag shoots after chemical desiccation of shoots in spring, a common horticultural practice in hop production conducted to set training timing and eliminate initial inoculum. Flag shoots were most numerous when plants were inoculated with P. macularis in early summer and, consequently, when powdery mildew was present throughout the entire period of crown bud development. The number of flag shoots produced was reduced from 6.8- to 46.6-fold when comparing the latest versus earliest inoculation dates. However, all inoculation timings yielded flag shoots at some level, suggesting that bud infection that occurs over an extended period of time in the previous season may allow the fungus to perennate. In studies in two commercial hop yards in Washington State, fungicide applications made after harvest reduced the level of powdery mildew on leaves in the current year but did not significantly reduce flag shoots in the following year. Given that bud infection occurred over a 10-week period, flag shoots developed even when plants were exposed to inoculum in October and some flag shoots survived chemical pruning practices, management efforts seem best directed to both preventative measures to reduce the likelihood of bud infection and remedial practices to physically eliminate infected crown buds in the ensuing year.


PROTEIN SYNTHESIS AND RNA SYNTHESIS DURING MITOSIS IN ANIMAL CELLS.
Protein synthesis and RNA synthesis during mitosis were studied by autoradiography on mammalian tissue culture cells. Protein synthesis was followed by incubating hamster epithelial and human amnion cells for 10 or 15 minutes with phenylalanine-C(14). To study RNA synthesis the hamster cells were incubated for 10 minutes with uridine-C(14). Comparisons of the synthetic capacity of the interphase and mitotic cells were then made using whole cell grain counts. The rate of RNA synthesis decreased during prophase and reached a low of 13 to 16 per cent of the average interphase rate during metaphase-anaphase. Protein synthesis in the hamster cells showed a 42 per cent increase during prophase with a subsequent return to the average interphase value during metaphase-anaphase. The human amnion cells showed no significant change at prophase but there was a 52 to 56 per cent drop in phenylalanine incorporation at metaphase-anaphase as compared to the average interphase rate. Colcemide was used on the hamster cells to study the effect of a prolonged mitotic condition on protein and RNA synthesis. Under this condition, uridine incorporation was extremely low whereas phenylalanine incorporation was still relatively high. The drastic reduction of RNA synthesis observed under mitotic conditions is believed to be due to the coiled condition of the chromosomes. The lack of a comparable reduction in protein synthesis during mitosis is interpreted as evidence for the presence in these cells of a relatively stable messenger RNA.


The role of nitric oxide on contractile impairment during endotoxemia in rat diaphragm muscle.
We examined the contribution of nitric oxide (NO) on the contractile impairment in diaphragm muscles of endotoxemic rats. Force-frequency relationship was depressed 24 h after lipopolysaccharide administration. 7-Nitroindazole, aminoguanidine and 1H-[1,2,4]Oxadiazole (4,3-a)quinoxalin-1-one (ODQ) partially restored the contractile impairment, Nomega-Nitro-L-Arginine (L-NNA) was ineffective. K+ contractions were reduced by 50% in endotoxemic muscles, 7-nitroindazole partially recovered, while aminoguanidine and L-NNA were ineffective. Verapamil reduced contractility to a greater extent in endotoxemic muscles. Caffeine and ryanodine contractions were augmented during endotoxemia without NOS contribution. L-NNA, 7-nitroindazole, ODQ and hemoglobin did not affect, but aminoguanidine completely restored partially inhibited neurotransmission by d-tubocurarine. Endotoxemia did not change membrane potentials and neurotransmitter release but slightly increased excitability. At this stage of endotoxemia, (1) constitutive NOS appears to be the dominant isoform, (2) NO does not have a major role on contractile dysfunction and (3) impairment could be explained by altered sensitivity of the voltage sensor. (4) NO does not substantially modulate neuromuscular transmission in normal and endotoxemic rats.


[The nurse as the last line of defence against quality defects in medicines].
The administration of medicines, the last stage in the process, is mainly carried out by the nurse. She is therefore the last person to be able to intercept any quality defects in the medication which, despite the stringent safety measures taken by pharmaceutical laboratories throughout their manufacturing processes, remain unavoidable. These interceptions are vital for the patient's safety.


Tracheal overexpression of IL-1β, IRAK-1 and TRAF-6 mRNA in obese-asthmatic male Wistar rats.
Human and animal studies have shown a close relationship between obesity and asthma severity. Here, we examined the effects of diet-induced obesity (DIO) on the expression levels of IL-1β, IRAK-1 and TRAF-6 mRNA in male Wistar rats tracheal after sensitization with ovalbumin (OVA). Twenty male Wistar rats divided to four groups, included, control group with normal diet (C+ND), OVA-sensitized group with normal diet (S+ND), control group with high-fat diet (C+HFD), and OVA-sensitized group with high-fat diet (S+HFD). All animals fed for 8 weeks with standard pelts or high-fat diet, and then were sensitized and challenged with OVA or saline for another 4 weeks with designed regimens. At the end of study, trachea isolated and examined for expression levels of IL-1β, IRAK-1 and TRAF-6 mRNA with RT-PCR method. Diet-induced obesity groups developed increased weight, obesity indexes and lipid profiles (P<0.05 to P<0.001). The expression levels of IL-1β mRNA in OVA-sensitization groups (S+ND and S+HFD) showed a significantly increased when compared with control group. Also in S+HFD group, expression level of TRAF-6 mRNA was higher than other groups (P<0.001). IRAK-1 expression level was high in S+HFD compared with control group.IL-1β and TRAF-6 mRNA correlated positively with obesity indexes. The results showed that DIO causes overexpression of IL-1β, IRAK-1 and TRAF-6 mRNA in an experimental model of asthma. Our results suggested that in obese-asthmatic conditions locally production and activation of pro-inflammatory agents can be increased. These findings showed that possible mechanism for obesity-asthma relationships.


Study of the three-way interaction between Trichoderma atroviride, plant and fungal pathogens by using a proteomic approach.
The main molecular factors involved in the complex interactions occurring between plants (bean), two different fungal pathogens (Botrytis cinerea, Rhizoctonia solani) and an antagonistic strain of the genus Trichoderma were investigated. Two-dimensional (2-D) electrophoresis was used to analyze separately collected proteomes from each single, two- or three-partner interaction (i.e., plant, pathogenic and antagonistic fungus alone and in all possible combinations). Differential proteins were subjected to mass spectrometry and in silico analysis to search for homologies with known proteins. In the plant proteome, specific pathogenesis-related proteins and other disease-related factors (i.e., potential resistance genes) seem to be associated with the interaction with either one of the two pathogens and/or T. atroviride. This finding is in agreement with the demonstrated ability of Trichoderma spp. to induce systemic resistance against various microbial pathogens. On the other side, many differential proteins obtained from the T. atroviride interaction proteome showed interesting homologies with a fungal hydrophobin, ABC transporters, etc. Virulence factors, like cyclophilins, were up-regulated in the pathogen proteome during the interaction with the plant alone or with the antagonist too. We isolated and confidently identified a large number of protein factors associated to the multi-player interactions examined.


An exploration of partnership through interactions between young 'expert' patients with cystic fibrosis and healthcare professionals.
To explore how young 'expert patients' living with Cystic Fibrosis and the healthcare professionals with whom they interact perceive partnership and negotiate care. Modern healthcare policy encourages partnership, engagement and self-management of long-term conditions. This philosophy is congruent with the model adopted in the care of those with Cystic Fibrosis, where self-management, trust and mutual respect are perceived to be integral to the development of the ongoing patient/professional relationship. Self-management is associated with the term; 'expert patient'; an individual with a long-term condition whose knowledge and skills are valued and used in partnership with healthcare professionals. However, the term 'expert patient' is debated in the literature as are the motivation for its use and the assumptions implicit in the term. A qualitative exploratory design informed by Interpretivism and Symbolic Interactionism was conducted. Thirty-four consultations were observed and 23 semi-structured interviews conducted between 10 patients, 2 carers and 12 healthcare professionals. Data were analysed thematically using the five stages of 'Framework' a matrix-based qualitative data analysis approach and were subject to peer review and respondent validation. The study received full ethical approval. Three main themes emerged; experiences of partnership, attributes of the expert patient and constructions of illness. Sub-themes of the 'ceremonial order of the clinic', negotiation and trust in relationships and perceptions of the expert patient are presented. The model of consultation may be a barrier to person-centred care. Healthcare professionals show leniency in negotiations, but do not always trust patients' accounts. The term 'expert patient' is unpopular and remains contested. Gaining insight into structures and processes that enable or inhibit partnership can lead to a collaborative approach to service redesign and a revision of the consultation model.


Does Hermansky-Pudlak syndrome predispose to systemic lupus erythematosus?
We report a Japanese patient with Hermansky-Pudlak syndrome (HPS) who developed systemic lupus erythematosus (SLE). This is the second case report of HPS complicated with SLE. A 1-bp duplication of adenine at codon 441 was found in the HPS gene, namely HPS1, which caused a frameshift. This case serves as evidence indicating that a patient with HPS can be predisposed to SLE.


[Case of cardiovascular syphilis].
The article presents a clinical case of cardiovascular syphilis in a 30-year old man. The authors provided a detailed clinical picture and results of laboratory and instrumental examinations. Tactics of managing patients with cardiovascular syphilis are addressed.


A systematic review of the effect of platelet-rich plasma on androgenetic alopecia of women.
Androgenetic alopecia (AGA) is the most common disease associated with hair loss in both females and males. Given the high prevalence of AGA and limited therapeutic methods and the high cost of hair transplantation and ease of use or platelet-rich plasma (PRP) therapies, this systematic review study was conducted to evaluate the effect of PRP on AGA of women. In this systematic review study, English-language articles were searched on PubMed, ISI web of knowledge, and Google Scholar by the end of 2019 with a combination of keywords. Finally, six articles were evaluated. The total number of subjects in this systematic review study was 92 people in six studies. All studies were clinical trials. Most of the studied had been conducted as a pilot study. Follow-up period for patients varied from 6 to 12 months. Except for one study, other studies have reported a positive therapeutic effect for PRP. The major limitation of the studies was the pilot nature and small sample size of these studies. According to the limited studies included in this systematic review, PRP treatment had a positive effect on the improvement of AGA, increasing hair density, and improving hair diameter in affected women.


Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88.
Toll-like receptor 4 (TLR4) plays a central role in host responses to bacterial infection, but the precise mechanism(s) by which its downstream signaling components coordinate the bone marrow response to sepsis is poorly understood. Using mice deficient in TLR4 downstream adapters MYD88 or TRIF, we demonstrate that both cell-autonomous and non-cell-autonomous MYD88 activation are major causes of myelosuppression during sepsis, while having a modest impact on hematopoietic stem cell (HSC) functions. In contrast, cell-intrinsic TRIF activation severely compromises HSC self-renewal without directly affecting myeloid cells. Lipopolysaccharide-induced activation of MYD88 or TRIF contributes to cell-cycle activation of HSC and induces rapid and permanent changes in transcriptional programs, as indicated by persistent downregulation of Spi1 and CebpA expression after transplantation. Thus, distinct mechanisms downstream of TLR4 signaling mediate myelosuppression and HSC exhaustion during sepsis through unique effects of MyD88 and TRIF.


A Rare Case of Blood Culture-Negative Isolated Pulmonic Valve Endocarditis Causing Empyema.
Right-sided native valve infective endocarditis (IE) refers to IE involving the tricuspid or pulmonic valve. The most common factors causing right-sided IE include intravenous drug use, intracardiac device, and central venous catheters. Isolated pulmonic valve IE has only been reported in less than 2% of all IE cases. We present a unique case of a patient with a history of poor oral hygiene found to have isolated blood culture-negative pulmonic valve IE, who subsequently developed empyema positive for Streptococcus constellatus.


Effects of the inducible nitric-oxide synthase inhibitor L-N(6)-(1-iminoethyl)-lysine on microcirculation and reactive nitrogen species generation in the kidney following lipopolysaccharide administration in mice.
The mortality rate for septic patients with acute renal failure is approximately doubled compared with patients with sepsis alone. Unfortunately, the treatment for sepsis-induced renal failure has advanced little during the last several decades. Because sepsis is often caused by lipopolysaccharide (LPS), a mouse model of LPS challenge was used to study the development of kidney injury. We hypothesized that inducible nitric-oxide synthase (iNOS)-catalyzed nitric oxide production and that generation of reactive nitrogen species (RNS) might play a role in the microcirculatory defect and resulting tubular injury associated with LPS administration. Fluorescent intravital videomicroscopy was used to assess renal peritubular capillary perfusion and document RNS generation by renal tubules in real time. As early as 6 h after LPS administration (10 mg/kg i.p.), RNS generation (rhodamine fluorescence), redox stress [NAD(P)H autofluorescence], and the percentage of capillaries without flow were each significantly increased compared with saline-treated mice (p < 0.05). The generation of RNS was supported by the detection of nitrotyrosine-protein adducts in the kidney using immunohistochemistry. The iNOS inhibitor l-N(6)-(1-iminoethyl)-lysine (l-NIL; 3 mg/kg i.p.) completely blocked the increase in rhodamine fluorescence and NAD(P)H autofluorescence and prevented the capillary defects at 6 h after LPS administration. These results suggest that iNOS-derived RNS is an important contributor to the peritubular capillary perfusion defects and RNS generation that occur during sepsis and emphasize that pharmacological inhibition of iNOS may provide beneficial effects during sepsis by improving renal capillary perfusion and reducing RNS generation in the kidney.


Abdominal pain: coronal reformations from isotropic voxels with 16-section CT--reader lesion detection and interpretation time.
To retrospectively assess if reader detection of intraabdominal pathologic findings on coronal reformations from isotropic voxels at 16-section computed tomography (CT) was similar to reader detection on transverse scans. The institutional review board approved this HIPAA-compliant study, and a waiver of informed consent was obtained. Twenty-nine consecutive patients (12 men, 17 women; mean age, 48 years; age range, 21-93 years) with abdominal pain underwent 16-section CT with coronal reformations. Eight independent readers reviewed randomized scans (transverse and coronal) and identified pathologic findings in multiple organ systems. Timing for each interpretation was recorded. One month later, readers reviewed the scan reformatted in the other imaging plane. Agreement between transverse and coronal scans was measured by using Cohen kappa coefficients. Agreement was moderate to near perfect between transverse and coronal interpretations for intraabdominal anatomic and pathologic findings (kappa=0.59-1.00). For transverse interpretations, more thoracic pathologic findings were noted than for coronal interpretations; for coronal interpretations, more lymph nodes were noted than for transverse interpretations. Mean transverse interpretation time was 4.9 minutes+/-1.1 (standard deviation) (range, 2.9-6.5 minutes); mean coronal interpretation time was 5.1 minutes+/-0.8 (range, 3.3-6.7 minutes). For each reader, there was no statistically significant difference in interpretation time between transverse and coronal scans (P=.06). With regard to the presence of intraabdominal pathologic findings, coronal reformations from isotropic voxels are similar to transverse scans in terms of interpretation time and reader agreement.


Updates and novel treatments in urothelial carcinoma.
Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease. Novel treatment approaches for UC have significantly impacted the management of patients. In 2016-2017, five immune checkpoint inhibitors marked a new paradigm in the treatment of UC for patients with advanced or metastatic disease or who are unable to tolerate platinum-based chemotherapy. Most recently, the U.S. Food and Drug Administration set restrictions on two commonly utilized checkpoint inhibitors, atezolizumab and pembrolizumab, in the first-line setting in patients with UC due to decreased survival associated with low expression of the protein programmed death ligand 1. Furthermore, Breakthrough Therapy Designations have been granted for enfortumab vedotin and erdafitinib for patients following platinum-based chemotherapy and those with fibroblast growth factor receptor mutated UC, respectively. Additional updates include dose-dense gemcitabine and cisplatin for muscle-invasive bladder cancer and preoperative checkpoint blockade. This article will review the available data on updates in the treatment of UC and future direction of therapies.


Release of amplified ribosomal DNA from the chromomeres of Acheta.
The major chromomeres of pachytene chromosomes 6 and 11 in the oocytes of Acheta (Orthoptera) are regions of amplification for ribosomal RNA cistrons (28 S and 18 S). During late prophase the amplified DNA copies are released from the chromomeres, which decrease in size as the amount of DNA decreases. The number of nucleotide pairs released from the major chromomere of chromosome 11 is about 1.38 x 10(9).


Identification of JAK/STAT pathway regulators--insights from RNAi screens.
While many core JAK/STAT pathway components have been discovered in Drosophila via classical genetic approaches, the identification of pathway regulators has been more challenging. Recently two cell-based RNAi screens for JAK/STAT pathway regulators have been undertaken using libraries of double-stranded RNAs targeting a large proportion of the predicted Drosophila transcriptome. While both screens identified multiple regulators, only relatively few loci are common to both data sets. Here we compare the two screens and discuss these differences. Although many factors are likely to be contributory, differences in the assay design are of key importance. Low levels of stimulation favouring the identification of negative pathway regulators and high levels of stimulation favouring the identification of positively acting factors. Ultimately, the results from both screens are likely to be largely complementary and have identified a range of novel candidate regulators of JAK/STAT pathway activity as a starting point for new research directions in the future.


Degradation of adenine nucleotides in ischemic and reperfused rat heart.
Complete cessation of flow in isolated rat hearts for 90 min resulted in a gradual breakdown of ATP and concomitant accumulation of degradation products, such as adenosine, inosine (major break-down product), hypoxanthine, and, to a lesser extent, xanthine. After 45 min of ischemia, the content and relative composition of purines hardly changed, whereas the AMP content continued to rise. This finding points to constraints on AMP degradation and flux through the degradation pathway from adenosine to uric acid in the ischemic heart. In myocardial preparations, the cells of which were deliberately disrupted by freezing and thawing before anoxic incubation, AMP did not accumulate and was finally converted to hypoxanthine. These results indicate that compartmentalization of substrates and enzymes is responsible for the observed preferential accumulation of AMP and inosine in the ischemic heart. Inhibition of hypoxanthine degradation is explained by the absence of oxygen. Restoration of flow and oxygen supply abolished the inhibition of metabolic flux. Accumulated purines were released into the coronary effluent and, concomitantly, further metabolized. Comparison of tissue levels of hypoxanthine, xanthine, and uric acid before reperfusion and the amounts released during reperfusion indicates that in rat myocardium substantial amounts of potentially hazardous xanthine oxidase-derived reactive oxygen species are likely to be formed during the early reperfusion phase.


The Surgical Management of Concomitant Gallbladder and Common Bile Duct Stones.
Background. The management of choledocholithiasis has evolved from open common bile duct exploration (OCBDE) to therapeutic endoscopic retrograde cholangiopancreatography (ERCP) to laparoscopic common bile duct exploration (LCBDE). Each entails a degree of difficulty. Aim. To review 5-year results of bile duct exploration in an UGI unit. Methods. Common bile duct explorations (CBDEs) performed between January 2008 and January 2013 were identified from a prospectively collected clinical audit system and results reviewed retrospectively. Results. 216 CBDEs were performed, 119 (55%) as an emergency and 52 (24%) following failed ERCP. Open CBDE (OCBDE) was performed primarily in 34/216 (16%) patients and attempted laparoscopically in 182 (84%). Fifty nine (32%) Laparoscopic CBDEs (LCBDEs) were converted to OCBDE. Of the remaining 123 LCBDEs, 51 (41%) primary choledochotomies and 72 (59%) primary transcystic CBDEs (TC-CBDEs) were performed. Forty nine (68%) TC-CBDEs were considered successful and 23 (32%) failed. Fifteen failed TC-CBDEs were converted to a successful laparoscopic choledochotomy. Ductal clearance was achieved in 187/216 (87%) patients and retained stones were identified in 20/123 (16%) LCBDEs. Complications occurred in 52/216 (24%) patients. There were 8/216 (4%) bile leaks requiring further intervention. Postoperative ERCP was carried out in 32/216 (15%) patients and 9/216 (4%) required relaparoscopy/laparotomy. No patient died. Conclusions. Successful management of choledocholithiasis requires a breadth of laparoscopic and endoscopic expertise.


STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells.
Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell lines (K562 and LAMA-84) than either drug alone (P < 0.01). Cell cycle analysis of propidium iodide-stained cells showed that STI-571 significantly reduced PBOX-6-induced G2M arrest and polyploid formation with a concomitant increase in apoptosis. Similar results were obtained in K562 CML cells using lead MTAs (paclitaxel and nocodazole) in combination with STI-571. Potentiation of PBOX-6-induced apoptosis by STI-571 was specific to Bcr-Abl-positive leukemia cells with no cytoxic effects observed on normal peripheral blood cells. The combined treatment of STI-571 and PBOX-6 was associated with the down-regulation of Bcr-Abl and repression of proteins involved in Bcr-Abl transformation, namely the antiapoptotic proteins Bcl-x(L) and Mcl-1. Importantly, PBOX-6/STI-571 combinations were also effective in STI-571-resistant cells. Together, these findings highlight the potential clinical benefits in simultaneously targeting the microtubules and the Bcr-Abl oncoprotein in STI-571-sensitive and -resistant CML cells.


[Meningeal carcinomatosis in breast cancer: from diagnosis to treatment].
The appearance of meningeal carcinomatosis in breast cancer is an event that is being reported increasingly more frequently in the literature. It seems to be related with the lengthening of the patients' lives, improved sensitivity to diagnostic imaging and impermeability of the blood-brain barrier to the chemotherapeutic agents. It is an evolutionary form that affirms the metastatic invasion of the subarachnoidal space and is correlated with limited survival. Its diagnosis is difficult, due to the lack of specificity of the clinical signs dominated by headaches, cognitive disorders and possible signs and symptoms of progressive focal lesions. Magnetic resonance imaging of the brain and the spinal cord interpreted by a specialist in neuro-oncology is the preferred examination in this indication, in the search for an increase in meningeal enhancement. Biological analysis of the cerebrospinal fluid is an essential element in the diagnosis. In addition to the biochemical study, the presence of neoplastic cells is in itself enough to confirm the diagnosis. False negatives are very common and represent an important diagnostic problem that entails the need to repeat the lumbar punctures. The therapeutic methods are standard, often invasive, dominated by intrathecal chemotherapy and are based on low-level scientific evidence. This study analyses the epidemiology, the prognostic factors, the diagnostic tools, currently available treatments and the possible future therapies of meningeal carcinomatosis in breast cancer.


Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart.
Nitric oxide (NO) has been noted to produce ischemic preconditioning (IPC)-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS) by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM). The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat. Experimental DM was induced by single dose of streptozotocin (50 mg/Kg, i.p,) and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H). Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC) staining, and release of lactate dehydrogenase (LDH) and creatin kinase-MB (CK-MB) in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent. IPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ) a caveolin inhibitor (0.2 mg/Kg/s.c), for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 μM/L), a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD), a mito KATP channel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination. Thus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in the diabetic myocardium, which may be due to up -regulation of caveolin and subsequently decreased activity of eNOS.


Identification of nucleoside transport binding sites in the human myocardium.
The role of nucleoside transport in ischemia-reperfusion injury and arrhythmias has been well documented in various animal models using selective blockers. However, clinical application of nucleoside transport inhibitors remains to be demonstrated in humans. It is not known whether human heart has nucleoside transport similar to that of animals. The aim of this study is to pharmacologically identify the presence of nucleoside transport binding sites in the human myocardium compared to animals. Myocardial tissue was obtained from guinea pig left and right ventricle, canine left ventricle, human intraoperative right atrium and human cadaveric right atrium and right and left ventricles. Myocardial preparations were obtained from tissue samples after homogenized and a differential centrifugation. Equilibrium binding assays were performed using [3H]-p-nitrobenzylthioinosine (NBMPR) at room temperature in the presence or absence of non-radioactive NBMPR or other nucleoside transport blockers such as p-nitrobenzylthioguanosine dipyridamole, lidoflazine, papaverin, adenosine and doxorubcine. From saturation curves and inhibition kinetics, we determined the relative maximal binding (Bmax) and dissociation constant (Kd) of [3H]-NBMPR binding of human myocardial preparations. Results demonstrated that the fresh human myocardial preparations have a specific binding site for NBMPR with a Bmax of 283+/-32 fmol/mg protein and Kd of 0.56+/-0.12 nM. These values are lower than those obtained from guinea pigs (Bmax = 1440+/-187 fmol/mg protein and Kd = 0.21+/-0.03 nM) and canine atrium (Bmax 594+/-73 fmol/mg protein, and Kd = 1.12+/-0.22 nM). Displacement kinetics studies revealed the relative potencies (of certain unrelated drugs as follow: p-nitrobenzylthioguanosine > dipyridamole > lidoflazine > pavaverine > Diltazam > adenosine > doxyrubicin. It is concluded that human myocardium contains an active nucleoside transport site which may play a crucial role in post-ischemic reperfusion-mediated injury in a wide spectrum of ischemic syndromes.


DNA replication and transcription direct a DNA strand bias in the process of targeted gene repair in mammalian cells.
The repair of point mutations can be directed by modified single-stranded DNA oligonucleotides and regulated by cellular activities including homologous recombination, mismatch repair and transcription. Now, we report that DNA replication modulates the gene repair process by influencing the frequency with which either DNA strand is corrected. An SV40-virus-based system was used to investigate the role of DNA synthesis on gene repair in COS-1 cells. We confirm that transcription exerts a strand bias on the gene repair process even when correction takes place on actively replicating templates. We were able to distinguish between the influences of transcription and replication on strand bias by changing the orientation of a gene encoding enhanced green fluorescent protein relative to the origin of replication, and confirmed the previously observed bias towards the untranscribed strand. We report that DNA replication can increase the level of untranscribed strand preference only if that strand also serves as the lagging strand in DNA synthesis. Furthermore, the effect of replication on gene repair frequency and strand bias appears to be independent of certain mismatched base pairs and oligonucleotide length.


Psoriasis disease severity measures: comparing efficacy of treatments for severe psoriasis.
Measurement of psoriasis disease severity and effectiveness of treatment involves both objective and subjective assessments.1 Comparing the efficacy of different treatments is complicated by the use of different metrics for measuring outcomes.2 Because these measures are not used routinely in clinical practice, interpreting these data, in particular assessing the degree of clinically meaningful improvement, is difficult. The drug approval process and product labeling reflect historical changes in standards of efficacy measurement.3 This paper reviews the metrics used to evaluate psoriasis treatment and compares available information on approved treatments for severe psoriasis. It further attempts to elucidate the value of these metrics and provide some guidance in properly evaluating the relative efficacy of current proven therapy with new treatments. While clinical trials are somewhat artificial, they provide proof that a drug is more effective than placebo. Efficacy in clinical practice, however, may be very different from the clinical trial setting. Comparison of efficacy under the current circumstances of varying evaluative metrics scales is possible with proper knowledge of the functionality of these methods.