Differential temperature-dependency of electrophysiological and inotropic actions of nifedipine, verapamil and cinnarizine in K+-depolarized ventricular myocardium.
1. Temperature dependency (in the range 27-37 degrees C) of inotropic and electrophysiological effects of equieffective (EC30 at 37 degrees C) concentrations of nifedipine, verapamil and cinnarizine was assessed in potassium depolarized isoprenaline-reactivated guinea-pig ventricular strips. 2. Lowering temperature greatly enhanced nifedipine inhibition of (a) maximal rate of depolarization (Vmax) of slow action potentials and (b) amplitude of contractions. 3. Electrophysiological and inotropic actions of verapamil was virtually unaffected by temperature changes. 4. Negative inotropic action of cinnarizine was greater at 37 degrees C than at lower temperature. At 37 degrees C, but not at 32 degrees C, cinnarizine reduced Vmax of slow action potentials.


Multibiomarker disease activity score and C-reactive protein in a cross-sectional observational study of patients with rheumatoid arthritis with and without concomitant fibromyalgia.
To examine the association between a multibiomarker disease activity (MBDA) score, CRP and clinical disease activity measures among RA patients with and without concomitant FM. In an observational cohort of patients with established RA, we performed a cross-sectional analysis comparing MBDA scores with CRP by rank correlation and cross-classification. MBDA scores, CRP and clinical measures of disease activity were compared between patients with RA alone and RA with concomitant FM (RA and FM) by univariate and multivariate analyses. CRP was ⩽1.0 mg/dl for 184 of 198 patients (93%). MBDA scores correlated with CRP (r = 0.755, P < 0.001), but were often discordant, being moderate or high for 19%, 55% and 87% of patients with CRP ⩽0.1, 0.1 to ⩽0.3, or 0.3 to ⩽1.0 mg/dl, respectively. Among patients with CRP ⩽1.0 mg/dl, swollen joint count (SJC) increased linearly across levels of MBDA score, both with (P = 0.021) and without (P = 0.004) adjustment for CRP, whereas CRP was not associated with SJC. The 28-joint-DAS-CRP, other composite measures, and their non-joint-count component measures were significantly greater for patients with RA and FM (n = 25) versus RA alone (n = 173) (all P ⩽ 0.005). MBDA scores and CRP were similar between groups. MBDA scores frequently indicated RA disease activity when CRP did not. Neither one was significantly greater among patients with RA and FM versus RA alone. Thus, MBDA score may be a useful objective measure for identifying RA patients with active inflammation when CRP is low (⩽1.0 mg/dl), including RA patients with concomitant FM.


Glucagon effects on the membrane potential and calcium uptake rate of rat liver mitochondria.
It has been widely reported that the in vivo administration of glucagon to rats results in the stimulation of calcium influx in subsequently isolated liver mitochondria. The mechanism of this effect is investigated through simultaneous measurements of calcium uptake rate and mitochondrial membrane potential. This allows the measurement of the calcium uniporter conductance independent of hormonal effects on electron transport or respiration. Two experimental approaches are used. The first involves measuring the uptake of 40-50 nmol of Ca2+/mg of mitochondrial protein with the calcium dye antipyrylazo III; the second uses 45Ca2+ to follow uptake in the presence of 0.5 to 1.5 microM free calcium, buffered with HEDTA. In both cases a tetraphenyl phosphonium electrode is used to follow membrane potential, and membrane potential is varied using either malonate or butylmalonate in the presence of rotenone. The relative merits of these two approaches are discussed. The conductance of the calcium uniporter is found not to be stimulated by glucagon pretreatment. Also, the relative glucagon stimulation of both calcium influx and membrane potential is found to increase with increasing malonate concentration. These results imply that there is no direct stimulation of calcium uptake into liver mitochondria following glucagon treatment. The results are consistent with a glucagon stimulation of substrate transport, substrate oxidation, or a stimulation of electron transport resulting in an increased membrane potential and secondary stimulation of calcium uptake.


Modification of pineapple peel fiber as metal ion adsorbent through reaction with succinic anhydride in pyridine and dimethyl sulfoxide solvents.
Reactions between saponified pineapple peel fiber (SPPF) and succinic anhydride were performed in refluxed pyridine and dimethyl sulfoxide to obtain modified pineapple peel fiber in pyridine (MPPF-PY) and modified pineapple peel fiber in dimethyl sulfoxide at room temperature (MPPF-DMRT) and at 70 degrees C (MPPF-DM70) as novel metal ionic adsorbents. The modified pineapple peel fibers were characterized by Fourier transform infrared (FTIR) and X-ray diffraction (XRD). The MPPF-PY, MPPF-DMRT, and MPPF-DM70 showed higher Cu2+, Cd2+, and Pb2+ adsorption capacity than raw pineapple peel fiber (RPPF) and SPPF. Dimethyl sulfoxide favored introduction of a carboxylic function group into pineapple peel fiber compared with pyridine. The elevated reaction temperature of dimethyl sulfoxide could increase the adsorption capacity of the modified pineapple fiber. Optimum pH values for Cu2+, Cd2+, and Pb2+ removal by MPPF-DM70 were pH 5.5, 7.5, and 5.5, respectively. The Cu2+, Cd2+, and Pb2+ adsorptions by MPPF-DM70 followed the pseudo second-order kinetics model and Langmuir model.


An overview of trends in animal poisoning cases in the United States: 2002-2010.
Veterinary toxicology is a constantly evolving field. The authors use the ASPCA Animal Poison Control Center's medical record database to examine recent trends in veterinary toxicology/animal poisoning incidents received from 2002 to 2010. The demographics of animals exposed to potentially harmful substances, the types of substances ingested, changes/emerging trends in substance exposures, and trends in therapies used to treat exposures are discussed.


The Role of Culture in Legal Languages, Legal Interpretation and Legal Translation.
The aim of this short essay is to highlight and concisely explore-but not address in depth-some cultural aspects related to legal languages, legal interpretation and legal translation. We would like to consider briefly the following questions: How can elements of legal language, as exemplified by proper names and euphemisms, be connected with cultural (extra-linguistic) factors influencing language units' formation? How can judicial discourse reflect the culture of a given justice system? How can the legal interpretation affect the degree of legal culture? Are theories of legal interpretation universal or applicable to specific legal cultures? What is the impact of culture on the context of legal translation? How can the cultural background affect the decision to use terms in translation? How does cyberculture impact legal translation?


Toxicity of cadmium oxide instilled into the rat lung. II. Inflammatory responses in broncho-alveolar lavage fluid.
Biochemical and cytological responses in the broncho-alveolar lavage fluid were investigated after instillation of cadmium oxide (CdO) or cadmium chloride (CdCl2) into the rat lung. Although biochemical responses of the lung to CdO were similar to the CdCl2-exposed lung, cytological response was more sensitive to CdO than CdCl2. Increases of lactate dehydrogenase, protein content and number of cells in the lavage fluid were proportional to the dose over the range of 0.5-10 micrograms Cd/rat. beta-Glucuronidase activity in the fluid increased with dose at low doses of Cd, but the activity did not continue to increase above 2 micrograms Cd/rat. A dose-response profile of phosphorus content in the lavage fluid, which might indicate amount of surfactant produced by Type II cells was similar to that observed for beta-glucuronidase in CdO-treated rats. Thus, tolerable level of instilled CdO for the rat lung was about 2 micrograms Cd/rat.


Further analysis of radiobiological parameters from the First and Second British Institute of Radiology randomized studies of larynx/pharynx radiotherapy.
This retrospective analysis of 1345 patients treated for cancer of the larynx or pharynx by randomization into two groups in each center in two separate trials of fractionated radiotherapy was carried out in an attempt to extract the radiobiological parameters alpha (dose), beta (fraction size), and gamma (overall time) from the data. Details of the trials have been published previously. In the first, 734 patients were randomized to either five or three fractions per week, in centers each using their own overall time, which varied from 3 to 7 weeks in different centers. In the second trial, 611 patients were randomized to "short" (< or = 4 weeks) or "long" (4-7 weeks) overall time. We combine the data from both studies and use the linear-quadratic formula with logistic regression and maximum-likelihood methods to obtain the radiobiological factors, taking into account other variables such as stage or age, when significant. The parameters calculated for local tumor control showed significant estimates of alpha, very small estimates of beta, and significant values of gamma. The derived estimates of alpha/beta were large, but very variable. The time-dose tradeoff--gamma/alpha was 0.76 Gy/day for larynx and 0.3 Gy/day for pharynx tumors (not significantly different from each other). Late complications gave indeterminate alpha/beta ratios and a time-dose factor not significantly different from zero. Acute normal-tissue effects gave alpha/beta estimates of 8-9 Gy and time factors of 0.8-0.9 Gy/day. The results are consistent with other published values with the exception that significant time factors for late complications could not be excluded.


Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model.
Recent efforts toward HIV vaccine development include the design of immunogens that can engage B cell receptors with the potential to affinity mature into broadly neutralizing antibodies (bnAbs). V2-apex bnAbs, which bind a protein-glycan region on HIV envelope glycoprotein (Env) trimer, are among the most broad and potent described. We show here that a rare "glycan hole" at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bnAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, we immunized wild-type rabbits with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response.


Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability.
Attempts to classify colorectal cancer into subtypes based upon molecular characterisation are overshadowed by the classical stepwise model in which the adenoma-carcinoma sequence serves as the morphological counterpart. Clarity is achieved when cancers showing DNA microsatellite instability (MSI) are distinguished as sporadic MSI-low (MSI-L), sporadic MSI-high (MSI-H) and hereditary non-polyposis colorectal cancer (HNPCC). Divergence of the 'methylator' pathway into MSI-L and MSI-H is at least partly determined by the respective silencing of MGMT and hMLH1. Multiple differences can be demonstrated between sporadic and familial (HNPCC) MSI-H colorectal cancer with respect to early mechanisms, evolution, molecular characterisation, demographics and morphology. By acknowledging the existence of multiple pathways, rapid advances in the fields of basic and translational research will occur and this will lead to improved strategies for the prevention, early detection and treatment of colorectal cancer.


Structural requirements for anthracycline-induced cardiotoxicity and antitumor effects.
By employing rat cardiac myocytes in culture and mouse L-1210 leukemia cells, we have compared different anthracycline analogs with respect to their ability to kill cardiac myocytes and tumor cells. Anthracyclines induced a decrease in cellular ATP and glutathione from both cardiac myocytes and L-1210 cells in a time- and concentration-dependent fashion. Moreover, the decrease in ATP in cardiac myocytes was followed by release of the cytoplasmic enzyme lactic acid dehydrogenase and of adenine nucleotides after anthracycline treatment. At very low concentrations of anthracyclines, at which ATP and glutathione were not affected, the drugs induced complete cessation of the growth of L-1210 cells. Some structural alterations in the anthracycline molecule resulted in parallel changes in antitumor activity and in cardiotoxicity. But other structural alterations resulted in dissimilar changes in antitumor activity and cardiotoxicity. Although the results indicate that the structural requirements for inducing cardiotoxicity and antitumor activity may be different, they also indicate that the mechanisms by which anthracycline causes cell death in tumor cells and cardiac myocytes may be the same.


Tumor lenvatinib addiction and withdrawal rebound response in patients with advanced endometrial cancer.
Combination therapy of lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), plus pembrolizumab, a monoclonal antibody targeting programmed death receptor 1 (PD-1), was recently approved by the Food and Drug Administration for therapy of advanced endometrial cancer. This case series highlights three patients with endometrial serous carcinoma who experienced disease stabilization or slow progression on lenvatinib plus pembrolizumab followed by rapid symptomatic growth of disease after lenvatinib discontinuation, and subsequent repeated response and symptom resolution after lenvatinib re-initiation. All patients died of disease complications 3 to 10 months after retreatment with lenvatinib. These observations highlight an important phenomenon of lenvatinib withdrawal rebound, likely driven by oncogenic signaling pathways upregulated in response to lenvatinib therapy. The findings of this case series represent a potential area for further research into the underlying mechanism for rebound and repeated response to lenvatinib, as well as strategies to mitigate disease flare related to lenvatinib withdrawal.


Complex Class 1 Integron in a Clinical Escherichia coli Strain From Vietnam Carrying Both mcr-1 and bla NDM-1.
The co-production of MCR and carbapenemase in Enterobacteriaceae has been previously reported. Here, we describe a clinical strain of Escherichia coli from Vietnam carrying both mcr-1 and bla NDM-1. Whole-genome sequencing showed that the genome of this strain consists of a 4,975,832-bp chromosome and four plasmids. The mcr-1 and bla NDM-1 genes are located on IncI2 and IncA/C2-type plasmids, respectively. Genetic analysis revealed the presence of a multidrug-resistant region with the structure of a novel complex class 1 integron including a class 1 integron region bearing two 5' conserved segments and one 3' conserved segment and two complete structures of ISCR1. The complex integron contains aminoglycoside resistance genes aadA2, aadB, strA, strB, and aphA6, quinolone resistance gene qnrA1, extended-spectrum β-lactamase gene bla OXA- 4, and a Tn125-like transposon bearing bla NDM-1. In addition, the dfrA12-gcuF-aadA2-cmlA1-aadA1-qacH gene cassette array belonging to the sul3-type integron was also identified, but the region found downstream of the gene cassette array is the IS440-tet(M)-IS26 element instead of the sul3 gene. The results further support that Enterobacteriaceae isolates co-harboring mcr and bla NDM are widely being distributed. The structural characteristics of the complex integron reveal that ISCR1 elements play an important role in the mobilization of bla NDM-1 and the development of multidrug-resistant regions.


Momentarily narcissistic? Development of a short, state version of the Pathological Narcissism Inventory applicable in momentary assessment.
Narcissism viewed as a personality process rather than a stable trait explains narcissistic functioning as a tool for maintaining a positive self-view. Studying narcissism therefore needs adequate momentary measures for collecting higher frequency longitudinal data in experience sampling method (ESM) studies. In this study, a shorter version of the Pathological Narcisissm Inventory is offered to measure vulnerable and grandiose narcissistic states, applicable in momentary assessment. The measurement tool was tested in three samples. First, we assessed the factor structure and associations with other contemporary measures of narcissism in a cross-sectional design on one English speaking (n = 319) and one Hungarian sample (n = 236). Second, we conducted a five-day long experience sampling method study with a total of 15 measurement points (n = 123). Based on structural equation modelling and multilevel analyses, the results suggest that the measure has adequate psychometric properties in both the within and between subject levels as well as acceptable convergent and discriminant validity. The Pathological Narcissism Inventory - State Version (PNI-S) can be a useful tool in momentary data collection enabling the examination of personality processes behind narcissistic functioning.


Phentolamine but not propranolol blocks the immunopotentiating effect of cold stress on antigen-specific IgM production in mice orally immunized with sheep red blood cells.
The effect of cold stress on immunocompetence was investigated in mice intragastrically intubated with sheep red blood cells. Cold stress was found to consistently augment total IgG and IgM production by splenic lymphocytes. In addition, antigen-specific IgM production by cultured splenic lymphocytes obtained from cold stressed animals was enhanced compared to unstressed mice. However, serum levels of total and antigen-specific immunoglobulins were suppressed or unaltered following cold stress. The alpha-adrenoceptor antagonist, phentolamine, could block the effects mediated by cold stress while the beta-adrenoceptor antagonist, propranolol, potentiated the action of cold stress. Taken together, the data indicate cold stress-mediated enhancement in immunoglobulin production by orally immunized animals takes place through the activation of alpha-adrenergic pathways. The results also suggest alpha- and beta-adrenergic pathways independently regulate antibody production following oral administration of antigen. These observations illustrate the integrative nature of the immune and neuroendocrine systems.


[A pedicled deep inferior epigastric flap to cover a hip arthroplasty infection].
The deep inferior epigastric perforator (DIEP) flap is a reliable flap mostly used in skin resurfacing after signifiant resection for sarcoma or correction contour deformities. This case is about a pedicled DIEP flap covering the trochanteric region after a total hip arthroplasty infection. A 62years old woman with a BMI at 42kg/m2 presents an infected total hip arthroplasty with a cutaneous defect. The hip prosthesis is changed and covered with a pedicled DIEP flap. This original case reports the used of pedicled DIEP flap in hip coverage. This local fasciocutaneous flap covered the hip osteoarticular infection. The limb is salved and the patient can walked again. The success of this surgery is the collaboration between infectious disease specialist, orthopedic surgeon and plastic surgeon.


Simultaneous growth and neutral lipid accumulation in microalgae.
In this paper the hypothesis was tested whether TAG accumulation serves as an energy sink when microalgae are exposed to an energy imbalance caused by nutrient limitation. In our continuous culture system, excess light absorption and growth-limiting nitrogen supply rates were combined, which resulted in accumulation of TAG (from 1.5% to 12.4% w/w) in visible lipid bodies in Neochloris oleoabundans, while cell replication was sustained. A fourfold increase in TAG productivity showed that TAG indeed served as an energy sink. However, the bulk of excess energy was dissipated leading to a significantly reduced biomass productivity and yield of biomass on light. This demonstrates that when aiming at industrial TAG production, sustaining efficient light energy use under nutrient stress is an important trait to look for in potential production organisms.


External Ventricular Drain Training in Medical Students Improves Procedural Accuracy and Attitudes Toward Virtual Reality.
Neurosurgery residents face a learning curve at the beginning of residency. Virtual reality (VR) training may alleviate challenges through an accessible, reusable, anatomical model. Medical students performed external ventricular drain placements in VR to characterize the learning curve from novice to proficient. Distance from catheter to foramen of Monro and location with respect to ventricle were recorded. Changes in attitudes toward VR were assessed. Neurosurgery residents performed external ventricular drain placements to validate proficiency benchmarks. Resident and student impressions of the VR model were compared. Twenty-one students with no neurosurgical experience and 8 neurosurgery residents participated. Student performance improved significantly from trial 1 to 3 (15 mm [12.1-20.70] vs. 9.7 [5.8-15.3], P = 0.02). Student attitudes regarding VR utility improved significantly posttrial. The distance to foramen of Monro was significantly shorter for residents than for students in trial 1 (9.05 [8.25-10.73] vs. 15 [12.1-20.70], P = 0.007) and trial 2 (7.45 [6.43-8.3] vs. 19.5 [10.9-27.6], P = 0.002). By trial 3 there was no significant difference (10.1 [8.63-10.95 vs. 9.7 [5.8-15.3], P = 0.62). Residents and students provided similarly positive feedback for VR in resident curricula, patient consent, preoperative practice and planning. Residents provided more neutral-to-negative feedback regarding skill development, model fidelity, instrument movement, and haptic feedback. Students showed significant improvement in procedural efficacy which may simulate resident experiential learning. Improvements in fidelity are needed before VR can become a preferred training technique in neurosurgery.


Trends in mammography screening rates after publication of the 2009 US Preventive Services Task Force recommendations.
In November 2009, the US Preventive Services Task Force (USPSTF) issued new recommendations regarding mammography screening. The Task Force recommended against routine screening for women ages 40 to 49 years and recommended biennial screening for women ages 50 to 74 years. The recommendations met great controversy in mass media and medical literature; whether they have had an impact on screening patterns is not known. The objective of this study was to determine whether the 2009 USPSTF recommendations led to changes in screening rates among women ages 40 to 49 years and ages 50 to 74 years. The authors performed cross-sectional assessments of mammography screening in 2005, 2008, and 2011 using data from the National Health Interview Survey, a nationally representative, in-person, household survey of the civilian, noninstitutionalized US population. In total, 27,829 women ages ≥ 40 years responded to the 2005, 2008, or 2011 surveys and reported about their mammography use. The primary outcome assessed was self-reported mammography screening in the past year. When adjusted for race, income, education level, insurance, and immigration status, mammography rates increased slightly from 2008 to 2011 (from 51.9% to 53.6%; P = .07) and did not decline within any age group. Among women ages 40 to 49 years, screening rates were 46.1% in 2008 and 47.5% in 2011 (P = 0.38). For women ages 50 to 74, screening rates were 57.2 in 2008 and 59.1 in 2011 (P = 0.09). Mammography rates did not decrease among women aged >40 years after publication of the USPSTF recommendations in 2009, suggesting that the vigorous policy debates and coverage in the media and medical literature have had an impact on the adoption of these recommendations.


Fetal development of the vesico-ureteric junction, and immunohistochemistry of the ends of refluxing ureters.
There is still misunderstanding about the normal fetal development of the vesico-ureteric junction (VUJ), the region that is most important for preventing VUR. There is little information on the causes of primary VUR and on the mechanisms of maturation of refluxing ureteric endings. Some studies show that the ratio of the intravesical ureteric length to diameter is obviously lower than had been assumed. It is doubtful that the length and course of the intravesical ureter is the sole factor in preventing reflux, as previously reported. The intravesical part of refluxing ureters shows dysplasia, atrophy and architectural derangement of smooth muscle fibres. A pathologically increased matrix remodelling combined with deprivation of the intramural nerve supply has been confirmed. Consequently, symmetrical contraction of the distal ureteric smooth muscle coat, creating the active valve mechanism to prevent reflux, is impossible. We reviewed publications using Medline, with the keywords 'human fetal development', 'embryology', 'ureterovesical junction', relevant 'growth data', 'vesico-ureteric reflux', 'children', 'immunohistochemistry', 'extracellular matrix', and 'nerve supply', respectively. Priority was given to articles that correlated specific embryological findings and basic research on possible mechanisms to the genesis and maturation of the VUJ.


Effects of morphine on cardiovascular responses to acute myocardial ischaemia in rats.
The effects of acute coronary artery ligation on cardiac rhythm and haemodynamics were studied in rats receiving either acute or chronic morphine-treatment. In chronic opiate-treated animals, increasing concentrations of morphine sulphate were administered in drinking water over a 3 week period, and the development of morphine tolerance and dependence was verified by decreased analgesic responses to morphine in the tail-immersion test and the occurrence of naloxone-precipitated withdrawal syndromes, respectively. Acute coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate, and ventricular tachycardia or fibrillation in anaesthetized rats. The changes in blood pressure and heart rate following acute coronary artery ligation were not significantly altered by acute or chronic morphine administration. The incidence and the time of onset of ventricular tachycardia or fibrillation were found to be significantly reduced and prolonged, respectively, in chronically morphine-treated rats, but were not significantly affected by acute morphine administration in naïve animals. These findings suggest that chronic morphine treatment lessens the occurrence of early ventricular arrhythmias caused by acute myocardial ischaemia in rats. The mechanism of this effect is unclear.


Safety, feasibility and effects of an individualised walking intervention for women undergoing chemotherapy for ovarian cancer: a pilot study.
Exercise interventions during adjuvant cancer therapy have been shown to increase functional capacity, relieve fatigue and distress and may assist rates of chemotherapy completion. These studies have been limited to breast, gastric and mixed cancer groups and it is not yet known if a similar intervention is even feasible among women with ovarian cancer. We aimed to assess safety, feasibility and potential effect of a walking intervention in women undergoing chemotherapy for ovarian cancer. Women newly diagnosed with ovarian cancer were recruited to participate in an individualised walking intervention throughout chemotherapy and were assessed pre- and post-intervention. Feasibility measures included session adherence, compliance with exercise physiologist prescribed walking targets and self-reported program acceptability. Changes in objective physical functioning (6-minute walk test), self-reported distress (Hospital Anxiety and Depression Scale), symptoms (Memorial Symptom Assessment Scale - Physical) and quality of life (Functional Assessment of Cancer Therapy - Ovarian) were calculated, and chemotherapy completion and adverse intervention effects recorded. Seventeen women were enrolled (63% recruitment rate). Mean age was 60 years (SD = 8 years), 88% were diagnosed with FIGO stage III or IV disease, 14 women underwent adjuvant and three neo-adjuvant chemotherapy. On average, women adhered to > 80% of their intervention sessions and complied with 76% of their walking targets, with the majority walking four days a week at moderate intensity for 30 minutes per session. Meaningful improvements were found in physical functioning, physical symptoms, physical well-being and ovarian cancer-specific quality of life. Most women (76%) completed ≥85% of their planned chemotherapy dose. There were no withdrawals or serious adverse events and all women reported the program as being helpful. These positive preliminary results suggest that this walking intervention for women receiving chemotherapy for ovarian cancer is safe, feasible and acceptable and could be used in development of future work. ACTRN12609000252213.


A Novel Mechanism for Generating the Interferon Signature in Lupus: Opsonization of Dead Cells by Complement and IgM.
In vitro studies suggest that the type I interferon (IFN) signature seen in most lupus patients results from Fcγ receptor-mediated uptake of nucleic acid-containing immune complexes by plasmacytoid dendritic cells and engagement of endosomal Toll-like receptors. The aim of this study was to reexamine the pathogenesis of the IFN signature in vivo. Lupus was induced in mice by injecting pristane. Some mice were treated with normal immunoglobulin or with cobra venom factor to deplete complement. The IFN signature was evaluated by polymerase chain reaction. The IFN signature also was determined in C4-deficient patients and control subjects. Wild-type C57BL/6 mice with pristane-induced lupus developed a strong IFN signature, which was absent in immunoglobulin-deficient (μMT), C3-/- , and CD18-/- mice. Intravenous infusion of normal IgM, but not IgG, restored the IFN signature in μMT mice, and the IFN signature in wild-type mice was inhibited by depleting complement, suggesting that opsonization by IgM and complement is involved in IFN production. Consistent with that possibility, the levels of "natural" IgM antibodies reactive with dead cells were increased in pristane-treated wild-type mice compared with untreated controls, and in vivo phagocytosis of dead cells was impaired in C3-deficient mice. To examine the clinical relevance of these findings, we identified 10 C4-deficient patients with lupus-like disease and compared them with 152 C4-intact patients and 21 healthy controls. In comparison with C4-intact patients, C4-deficient patients had a different clinical/serologic phenotype and lacked the IFN signature. These studies define previously unrecognized roles of natural IgM, complement, and complement receptors in generating the IFN signature in lupus.


Failure of lysine-acetylsalicylate and phenylbutazone to affect gastrin secretion in healthy adults.
The effect of acute parenteral and chronic oral administration of lysine-acetylsalicylate and phenylbutazone on fasting and meal-stimulated serum gastrin levels was investigated in healthy volunteers. No significant changes in gastrin secretion were induced by any treatment. The results confirm and extend previous observations suggesting that the ulcerogenic properties of salicylates and phenylbutazone are not related to increased gastrin secretion.


Role of GTP hydrolysis in fission of caveolae directly from plasma membranes.
Caveolae are specialized invaginated cell surface microdomains of undefined function. A cell-free system that reconstituted fission of caveolae from lung endothelial plasma membranes was developed. Addition of cytosol and the hydrolysis of guanosine triphosphate (GTP) induced caveolar fission. The budded caveolae were isolated as vesicles rich in caveolin and the sialoglycolipid GM1 but not glycosyl-phosphatidylinositol (GPI)-anchored proteins. These vesicles contained the molecular machinery for endocytosis and transcytosis. In permeabilized endothelial cells, GTP stimulated, whereas GTPgammaS prevented, caveolar budding and endocytosis of the cholera toxin B chain to endosomes. Thus, caveolae may bud to form discrete carrier vesicles that participate in membrane trafficking.


Does prone positioning reduce small bowel dose in pelvic radiation with intensity-modulated radiotherapy for gynecologic cancer?
Intensity-modulated radiotherapy (IMRT) has been shown to reduce the radiation dose to small bowel in pelvic RT in gynecology patients. Prone positioning has also been used to decrease small bowel dose by displacement of small bowel from the RT field in these patients. The purpose of this study was to determine whether the combination of both IMRT and prone positioning on a belly board can reduce small bowel dose further in gynecologic cancer patients undergoing pelvic RT. IMRT plans for pelvic RT were computed in 16 patients with gynecologic cancer who had undergone planning CT scans in both the supine and the prone positions on a belly board. For the gross tumor volume, the uterus, cervix, and tumor (or postoperative region) were traced. The clinical target volume was defined as the vessels and lymph nodes from the obturator level to the aortic bifurcation, presacral region, and upper 4 cm of the vagina, in addition to gross tumor volume. The planning target volume was defined as a 2-cm margin in addition to the gross tumor volume and upper 4 cm of the vagina, and 1.5 cm for lymph nodes and vessels. Normal tissue regions of interest included small bowel, large bowel, and bladder. IMRT plans using (1) the limited arc technique (180 degrees arc length) and (2) the extended arc technique (340 degrees arc length) were computed. Dose-volume histograms for normal tissue structures and target were compared between the supine and prone IMRT plans using the paired t test. Prone positioning on a belly board decreased the small bowel dose in gynecologic pelvic IMRT, and the magnitude of improvement depended on the specific IMRT technique used. With the limited arc technique, prone positioning significantly decreased the irradiated small bowel volume at the 25-50-Gy dose levels compared with supine positioning. Small bowel volumes receiving > or =45 Gy decreased from 19% to 12.5% (p = 0.005) with prone positioning. With the extended arc technique, the decrease in irradiated small bowel volume was less marked, but remained detectable in the 35-45-Gy dose levels. Small bowel volumes receiving > or =45 Gy decreased from 13.6% to 10.1% (p = 0.03) with prone positioning. The effect of prone positioning on large bowel and bladder was variable. Large bowel volumes receiving > or =45 Gy increased with prone positioning from 16.5% to 20.6% (p = 0.02) in the limited arc technique and was unaffected in the extended arc technique. These preliminary data suggest that prone positioning on a belly board can reduce the small bowel dose further in gynecology patients treated with pelvic RT, and that the dose reduction depends on the IMRT technique used.


CO2 Biofixation by the Cyanobacterium Spirulina sp. LEB 18 and the Green Alga Chlorella fusca LEB 111 Grown Using Gas Effluents and Solid Residues of Thermoelectric Origin.
The concentration of carbon dioxide (CO2) in the atmosphere has increased from 280 to 400 ppm in the last 10 years, and the coal-fired power plants are responsible for approximately 22 % of these emissions. The burning of fossil fuel also produces a great amount of solid waste that causes serious industrial and environmental problems. The biological processes become interesting alternative in combating pollution and developing new products. The objective of this study was to evaluate the CO2 biofixation potential of microalgae that were grown using gaseous effluents and solid residues of thermoelectric origin. The microalgae Chlorella fusca LEB 111 presented higher rate of CO2 biofixation (42.8 %) (p < 0.01) than did Spirulina sp. LEB 18. The values for the CO2 biofixation rates and the kinetic parameters of Spirulina and Chlorella cells grown using combustion gas did not differ significantly from those of cells grown using CO2 and a carbon source in the culture media. These microalgae could be grown using ash derived from coal combustion, using the minerals present in this residue as the source of the essential metals required for their growth and the CO2 derived from the combustion gas as their carbon source.


[Synergistic Antibacterial Activity of Berberine in Combination with Amylmetacresol Against Enterococcus faecalis in vitro].
To study the antibacterial effect of berberine combined with amylmetacresol on Enterococcus faecalis. Both dilution method and live bacteria CFU were used to determine the minimum inhibitory concentration (MIC) of berberine and amylmetacresol on E. faecalis. The killing effect of berberine and amylmetacresol on planktonic E. faecalis was detected by suspension quantitative germicidal test and live/dead bacteria staining. The effects of berberine and amylmetacresol on the structure of mature biofilm of E. faecalis was observed by scanning electron microscopy (SEM). The toxicity of berberine and amylmetacresol on human oral keratinocytes (HOK) was determined by CCK-8 cell proliferation and cytotoxicity assay and cytotoxicity LDH assay. The MIC of berberine was 512 μg/mL, and the MIC of amylmetacresol was 0.023 3%. 512 μg/mL berberine and 0.002 33% amylmetacresol had a weak killing effect on planktonic E. faecalis alone, while they showed a synergistic antibacterial effect in combination. Cell survival in the biofilm was only slightly changed by berberine and amylmetacresol. The structure of biofilm was obviously changed by berberine and amylmetacresol. 512 μg/mL berberine and 0.002 33% amylmetacresol alone or in combination showed the survival rate was much higher than the injury rate, suggesting berberine and amylmetacresol had a low cytotoxicity. Berberine and amylmetacresol had synergism against E. faecalis, and the biological safety of the combination use was better.


Spinal Arachnoid Cyst Analysis of Surgical Experience in a Single Tertiary Care Centre and Review of Literature.
To study patients with spinal arachnoid cysts, who underwent cyst excision with dural defect repair or marsupialization, and their outcomes. The retrospective analysis involved reviewing the records of 38 patients who underwent surgical treatment for spinal arachnoid cysts in the Department of Neurosurgery at Christian Medical College, Vellore, between August 2004 and December 2022. The study examined the demographics, clinical presentation, imaging, surgical intervention, and outcomes of these patients. The majority of patients in the study were male (29/38, with 76.3%) and the thoracic region was the most common location for the cyst (17, with 44.7%). Weakness was the primary complaint and 94.7% of patients had myelopathy. The bladder was affected in 13 patients (34.2%). Of the 38 patients, 26 (71%) had cysts in extradural locations, while the rest were intradural. In total, 45.5% of intradural cysts were located in the ventral region. Seventeen (65.4%) had dural defects along the root sleeve and 29 (76.3%) underwent complete excision. All extradural cysts underwent complete excision and repair of the dural defect. Thirty patients (78.9%) experienced improved outcomes with reduced spasticity and improved weakness. One patient developed new-onset weakness postoperatively due to epidural hematoma. The mean follow-up period was 41 months and one patient experienced a recurrence. Spinal arachnoid cyst is a rare benign spinal condition that is typically treated with surgery in symptomatic patients. Surgical intervention may involve either the excision of the cyst or marsupialization.


Monogalactosyldiacylglycerols with High PUFA Content From Microalgae for Value-Added Products.
Monogalactosyldiacylglycerols (MGDGs) from microalgae containing a high proportion of polyunsaturated fatty acids (PUFAs) have enormous potential applications in various industries. In this study, the productivity and fatty acid composition of MGDGs from three microalgae in commercialized production, Chlorella sorokiniana GT, Nannochloropsis oceanica IMET1, and Arthrospira platensis, were evaluated under nitrogen-sufficient (+N) and nitrogen-deficient (-N) conditions. Under +N conditions, higher productivities of MGDGs from C. sorokiniana GT1, N. oceanica IMET1, and A. platensis were obtained with 16.3, 4.3, and 1.3 mg/L/day, respectively. In agreement with a high ratio of PUFAs in MGDGs, they accounted for 56%, 66%, and 47% of the total fatty acids in MGDG correspondingly. α-linoleic acid (ALA), eicosapentaenoic acid (EPA), and γ-linoleic acid (GLA) were the specific PUFAs of the three microalgae. The proportions of the specific PUFAs in MGDG accounted for 26%, 44%, and 63% of total specific PUFAs, respectively. Considering the production, cost of microalgae biomass and price of MGDG, the commercialized microalgae C. sorokiniana GT1 and A. platensis showed great potential to produce MGDGs with a high content of PUFAs, in contrast to N. oceanica IMET1, with its high biomass cost and low production. This study provides basic data for the extraction and separation of microalgae lipids from commercialized microalgae, which is helpful to promote the commercialization of microalgae.


Pediatric severe asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines.
The pathology of pediatric severe therapy-resistant asthma (STRA) is little understood. We hypothesized that STRA in children is characterized by airway eosinophilia and mast cell inflammation and is driven by the T(H)2 cytokines IL-4, IL-5, and IL-13. Sixty-nine children (mean age, 11.8 years; interquartile range, 5.6-17.3 years; patients with STRA, n = 53; control subjects, n = 16) underwent fiberoptic bronchoscopy, bronchoalveolar lavage (BAL), and endobronchial biopsy. Airway inflammation, remodeling, and BAL fluid and biopsy specimen T(H)2 cytokines were quantified. Children with STRA also underwent symptom assessment (Asthma Control Test), spirometry, exhaled nitric oxide and induced sputum evaluation. Children with STRA had significantly increased BAL fluid and biopsy specimen eosinophil counts compared with those found in control subjects (BAL fluid, P < .001; biopsy specimen, P < .01); within the STRA group, there was marked between-patient variability in eosinophilia. Submucosal mast cell, neutrophil, and lymphocyte counts were similar in both groups. Reticular basement membrane thickness and airway smooth muscle were increased in patients with STRA compared with those found in control subjects (P < .0001 and P < .001, respectively). There was no increase in BAL fluid IL-4, IL-5, or IL-13 levels in patients with STRA compared with control subjects, and these cytokines were rarely detected in induced sputum. Biopsy IL-5(+) and IL-13(+) cell counts were also not higher in patients with STRA compared with those seen in control subjects. The subgroup (n = 15) of children with STRA with detectable BAL fluid T(H)2 cytokines had significantly lower lung function than those with undetectable BAL fluid T(H)2 cytokines. STRA in children was characterized by remodeling and variable airway eosinophil counts. However, unlike in adults, there was no neutrophilia, and despite the wide range in eosinophil counts, the T(H)2 mediators that are thought to drive allergic asthma were mostly absent.


Acceptability, safety, and patterns of use of oral tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis in South African adolescents: an open-label single-arm phase 2 trial.
HIV incidence among adolescents in southern Africa remains unacceptably high. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention but there are few data on its implementation among adolescents. We aimed to investigate the safety, feasibility, and acceptability of PrEP with oral tenofovir disoproxil fumarate and emtricitabine as part of a comprehensive HIV prevention package in an adolescent population in South Africa. This open-label single-arm phase 2 study (PlusPills) was done in two research clinics in Cape Town and Johannesburg, South Africa. Adolescents aged 15-19 years were recruited into the study through recruitment events and outreach in the community. Potential participants were eligible for enrolment if they reported being sexually active. Exclusion criteria were a positive test for HIV or pregnancy at enrolment, breastfeeding, or any relevant co-morbidities. Participants were given oral tenofovir disoproxil fumarate and emtricitabine for PrEP to take daily for the first 12 weeks and were then given the choice to opt in or out of PrEP use at three monthly intervals during scheduled clinic visits. Participants were invited to monthly visits for adherence counselling and HIV testing during the study period. The primary outcomes were acceptability, use, and safety of PrEP. Acceptability was measured by the proportion of participants who reported willingness to take up PrEP and remain on PrEP at each study timepoint. Use was defined as the number of participants who continued to use PrEP after the initial 12-week period until the end of the study (week 48). Safety was measured by grade 2, 3, and 4 laboratory and clinical adverse events using the Division of AIDS table for grading the severity of adult and paediatric adverse events, version 1.0. Dried blood spot samples were collected at each study time-point to measure tenofovir diphosphate concentrations. This trial is registered with ClinicalTrials.gov, NCT02213328. Between April 28, 2015, and Nov 11, 2016, 244 participants were screened, and 148 participants were enrolled (median age was 18 years; 99 participants [67%] were female) and initiated PrEP. PrEP was stopped by 26 of the 148 (18%) participants at 12 weeks. Cumulative PrEP opt-out, from the total cohort, was 41% (60 of 148 participants) at week 24 and 43% (63 of 148 participants) at week 36. PrEP was well tolerated with only minor adverse events (grade 2) thought to be related to study drug, which included headache (n=4, 3%), gastrointestinal upset (n=8, 5%), and skin rash (n=2, 1%). Two participants (1%) experienced grade 3 weight loss, which was deemed related to the study drug and resolved fully when PrEP was discontinued. Tenofovir diphosphate concentrations were detectable (>16 fmol/punch) in dried blood spot samples in 108 (92%) of 118 participants who reported PrEP use at week 12, in 74 (74%) of 100 participants at week 24, and in 22 (59%) of 37 participants by the study end at week 48. In this cohort of self-selected South African adolescents at risk of HIV acquisition, PrEP appears safe and tolerable in those who continued use. PrEP use decreased throughout the course of the study as the number of planned study visits declined. Adolescents in southern Africa needs access to PrEP with tailored adherence support and possibly the option for more frequent and flexible visit schedules. National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.


[Use of biochemical indices in the classification of Sporozoa].
The paper presents a survey of literary and author's own data on metabolism of nitric bases, nucleosides and orotic acid in Eimeria, Toxoplasma and Plasmodium. Experimental data on nucleotide content of DNA, fractional content of ribosome RNA, isofermental spectrum of a number of oxidation-reduction enzymes and immunochemical analysis of antigens in various groups of Sporozoa (Eimeria, Toxoplasma and Plasmodium) are given. A possible use of biochemical and immunochemical data for the taxonomy of Sporozoa is suggested.


The quantification of body fluid allostasis during exercise.
The prescription of an optimal fluid intake during exercise has been a controversial subject in sports science for at least the past decade. Only recently have guidelines evolved from 'blanket' prescriptions to more individualised recommendations. Currently the American College of Sports Medicine advise that sufficient fluid should be ingested to ensure that body mass (BM) loss during exercise does not exceed >2 % of starting BM so that exercise-associated medical complications will be avoided. Historically, BM changes have been used as a surrogate for fluid loss during exercise. It would be helpful to accurately determine fluid shifts in the body in order to provide physiologically appropriate fluid intake advice. The measurement of total body water via D2O is the most accurate measure to detect changes in body fluid content; other methods, including bioelectrical impedance, are less accurate. Thus, the aim of this review is to convey the current understanding of body fluid allostasis during exercise when drinking according to the dictates of thirst (ad libitum). This review examines the basis for fluid intake prescription with the use of BM, the concepts of 'voluntary and involuntary dehydration' and the major routes by which the body gains and loses fluid during exercise.


[Treatment of benign prostatic hyperplasia with laser through the endoscope].
To evaluate the effect of transurethral laser prostatectomy (TULP) and its relation with the size of prostate. 469 benign prostatic hyperplasia receiving TULP from 1988 to 1998 were reviewed retrospectively, and the methods of operation and preoperative and postoperative symptom were compared. The effect of 233 patients undergoing TULP was compared with the size of the prostate. The average value for IPSS of 469 patients decreased from 26.7 (preoperation) to 14.2 (postoperation). The mean value of maximum uroflow rate increased from 6.2 ml/s (preoperation) to 11.8 ml/s (postoperation). No difference was seen in postoperative effect between the transurethral contact and noncontact laser prostatectomy. If the estimating weight of prostate exceeded 50 g, the maximum flow rate after 3 years was decreased evidently, the value of IPSS increased to over 20. If the estimating weight of prostate is less than 50 g, TULP is indicated.


A routine method for diagnosis of early myocardial infarction.
We compared Barbeito-Lopez Trichrome stain with H-E, the basic fuchsin picric acid and Nitro Blue of Tetrazolium stains. The Barbeito-Lopez Trichrome stain was much more sensitive than the other stains for the diagnosis of early myocardial coagulation necrosis.


Mitochondrial transplantation enhances murine lung viability and recovery after ischemia-reperfusion injury.
The most common cause of acute lung injury is ischemia-reperfusion injury (IRI), during which mitochondrial damage occurs. We have previously demonstrated that mitochondrial transplantation is an efficacious therapy to replace or augment mitochondria damaged by IRI, allowing for enhanced muscle viability and function in cardiac tissue. Here, we investigate the efficacy of mitochondrial transplantation in a murine lung IRI model using male C57BL/6J mice. Transient ischemia was induced by applying a microvascular clamp on the left hilum for 2 h. Upon reperfusion mice received either vehicle or vehicle-containing mitochondria either by vascular delivery (Mito V) through the pulmonary artery or by aerosol delivery (Mito Neb) via the trachea (nebulization). Sham control mice underwent thoracotomy without hilar clamping and were ventilated for 2 h before returning to the cage. After 24 h recovery, lung mechanics were assessed and lungs were collected for analysis. Our results demonstrated that at 24 h of reperfusion, dynamic compliance and inspiratory capacity were significantly increased and resistance, tissue damping, elastance, and peak inspiratory pressure (Mito V only) were significantly decreased (P < 0.05) in Mito groups as compared with their respective vehicle groups. Neutrophil infiltration, interstitial edema, and apoptosis were significantly decreased (P < 0.05) in Mito groups as compared with vehicles. No significant differences in cytokines and chemokines between groups were shown. All lung mechanics results in Mito groups except peak inspiratory pressure in Mito Neb showed no significant differences (P > 0.05) as compared with Sham. These results conclude that mitochondrial transplantation by vascular delivery or nebulization improves lung mechanics and decreases lung tissue injury.


Neighbor cells restrain furrowing during epithelial cytokinesis.
Cytokinesis challenges epithelial tissue homeostasis by generating forces that pull on neighboring cells via cell-cell junctions. Previous work has shown that junction reinforcement at the furrow in Xenopus laevis epithelia regulates the speed of furrowing1. This suggests the cytokinetic array that drives cell division is subject to resistive forces from epithelial neighbor cells. We show here that contractility factors accumulate in neighboring cells near the furrow during cytokinesis. Additionally, increasing neighbor cell stiffness, via ɑ-actinin overexpression, or contractility, through optogenetic Rho activation in one neighbor cell, slows or asymmetrically pauses furrowing, respectively. Notably, optogenetic stimulation of neighbor cell contractility on both sides of the furrow induces cytokinetic failure and binucleation. We conclude that forces from the cytokinetic array in the dividing cell are carefully balanced with restraining forces generated by neighbor cells, and neighbor cell mechanics regulate the speed and success of cytokinesis.


The independent effects of local heat application on muscle growth program associated mRNA and protein phosphorylation.
The development and maintenance of skeletal muscle is crucial for the support of daily function. Recent evidence suggests that genes coded for proteins associated with the human muscle growth program (myogenic and proteolytic genes) are sensitive to local heat application. Therefore, the purpose of this investigation was to determine the effect of 4 h of local heat application to the vastus lateralis at rest on acute phosphorylation (mTORSer2448, p70-S6K1Thr389, and 4E-BP1Thr47/36) and gene expression changes for proteins associated with the muscle growth program. Intramuscular temperature of the HOT limb was 1.2 ± 0.2 °C higher than CON limb after 4 h of local heating. However, this local heat stimulus did not influence transcription of genes associated with myogenesis (MSTN, p = 0.321; MYF5, p = 0.445; MYF6, p = 0.895; MEF2a, p = 0.809; MYO-G, p = 0.766; MYO-D1, p = 0.118; RPS3, p = 0.321; and RPL-3L, p = 0.577), proteolysis (Atrogin-1, p = 0.573; FOXO3a, p = 0.452; MURF-1, p = 0.284), nor protein phosphorylation (mTORSer2448, p = 0.981; P70-S6K1Thr389, p = 0.583; 4E-BP1Thr37/46, p = 0.238) associated with the muscle growth program. These findings suggest little to no association between the local application of heat, at rest, and the activation of the observed muscle growth program-related markers.


Tracheoesophageal fistula length decreases over time.
The objectives of this study were to demonstrate that the length of the tracheoesophageal voice prosthesis changes over time and to determine whether the prosthesis length over time increased, decreased, or showed no predictable change in size. A retrospective chart review was performed at a tertiary care referral center. Patients who underwent either primary or secondary tracheoesophageal puncture between January 2006 and August 2014 were evaluated. Patients were excluded if the tracheoesophageal prosthesis size was not consistently recorded or if they required re-puncturing for an extruded prosthesis. Data analyzed included patient demographics and the length of the tracheoesophageal voice prosthesis at each change. A total of 37 patients were identified. The mean age was 64 years. Seventy-six percent were male. 24 % underwent primary tracheoesophageal puncture and 76 % underwent secondary tracheoesophageal puncture. The length of the prosthesis decreased over time (median Kendall correlation coefficient = -0.60; mean = -0.44) and this correlation between length and time was significant (p = 0.00085). Therefore, in conclusion, tracheoesophageal prosthesis length is not constant over time. The tracheoesophageal wall thins, necessitating placement of shorter prostheses over time. Patients with a tracheoesophageal voice prosthesis will require long-term follow-up and repeat sizing of their prosthesis. Successful tracheoesophageal voicing will require periodic reevaluation of these devices, and insurers must, therefore, understand that long-term professional care will be required to manage these patients and their prostheses.


Prostate Cancer Outcomes Following Solid-Organ Transplantation: A SEER-Medicare Analysis.
Immunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low-risk features would ordinarily justify active surveillance. Using SEER-Medicare, we identified 163 676 men aged 66 years and older diagnosed with nonmetastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to nontransplanted controls by age, race, region, year, T-stage, grade, comorbidity, and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific mortality (PCSM) and overall mortality (OM). We identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3100 men. At 10 years, OM was 55.7% and PCSM was 6.0% in the transplant cohort compared with 42.4% (P < .001) and 7.6% (P = .70) in the nontransplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (hazard ratio = 0.88, 95% confidence interval = 0.61 to 1.27, P = .70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well or moderately differentiated "low-risk" prostate cancer, PCSM was similar for treated and untreated men (hazard ratio = 0.92, 95% confidence interval = 0.47 to 1.81). Among men aged 66 years and older with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.


The effect of multiple allergen immunotherapy on exhaled nitric oxide in adults with allergic rhinitis.
There is a lack of objective measures of the clinical efficacy of allergen immunotherapy which relies on patients' perception about the effect of this treatment. We studied whether the fraction of exhaled nitric oxide is affected by multiple allergen immunotherapy in polysensitized adult subjects with allergic rhinitis. We also looked for associations between exhaled nitric oxide and subjects' demographics, symptom scores, and pulmonary function tests. Twenty adult, polysensitized subjects with seasonal and perennial allergic rhinitis who chose to undergo allergen immunotherapy were enrolled. They were evaluated at baseline, and 4, 8, 12, 24, and 52 weeks later. Exhaled nitric oxide was reported as the mean of triplicate determinations. Our results indicate that multiple allergen immunotherapy did not affect exhaled nitric oxide levels and such levels did not correlate with subjects' demographics and pulmonary function tests. However, exhaled nitric oxide was associated with rhinoconjuctivitis and asthma symptom scores at the end of the study. In polysensitized adult subjects with allergic rhinitis, exhaled nitric oxide levels are unaffected by multiple allergen immunotherapy.


Nucleoside deoxyribosyltransferase-II from Lactobacillus helveticus Substrate specificity studied. Pyrimidine bases as acceptors.
The nucleoside deoxyribosyltransferase (nucleoside:purine (pyrimidine) deoxyribosyltransferase, EC 18.104.22.168) fraction catalyzing specifically the transfer of the deoxyribosyl moiety from a purine (or a pyrimidine) to a pyrimidine (or a purine) exhibits a broad specificity for the acceptor base. With a pyrimidine base as the acceptor a -OH or -SH group adjacent to the N-1 atom is essential. A substituent on position 6 hinders the reaction. On positions 4 and 5 various substituent were found to influence the reaction rate and some of them give non-competent substrates. A few anomalous cases are also discussed in relation with the role of N-3. Deoxyribonucleosides can also be obtained with non-pyrimidine rings.


Using Fluorescence Recovery After Photobleaching (FRAP) to Study Dynamics of the Structural Maintenance of Chromosome (SMC) Complex In Vivo.
The SMC complex, MukBEF, is important for chromosome organization and segregation in Escherichia coli. Fluorescently tagged MukBEF forms distinct spots (or "foci") in the cell, where it is thought to carry out most of its chromosome associated activities. This chapter outlines the technique of Fluorescence Recovery After Photobleaching (FRAP) as a method to study the properties of YFP-tagged MukB in fluorescent foci. This method can provide important insight into the dynamics of MukB on DNA and be used to study its biochemical properties in vivo.


Analysis of a maritime transport chain with information asymmetry and disruption risk.
Maritime transport chain is facing huge information asymmetry after the outbreak of major emergencies, such as COVID-19 epidemic. The previous literature has proved that information investing and information sharing are two effective tactics to relieve information asymmetry between supply chain nodes, and help them improve the performance of the supply chain. This paper assumes random demand disruption is the main cause of the information asymmetry in a maritime transportation chain. To explore how the random demand disruption and channel competition jointly impact operational decisions in a dual-channel maritime transport chain composed of one port, two carriers and shippers, we construct a game-theoretical basic model, and proposed two strategies, i.e., information investing and information sharing. Several significant managerial insights are derived. First, we find that inaccurate disruption information leads to inaccurate decisions and huge losses; Second, investing in precise information benefits the port only if the chain members are optimistic about the market, and improves the revenue of the carrier who invested in information if the investment cost is reasonable; Third, accepting information sharing benefits the port only when the precise disruption and the distortion of information are relatively large, as well as the misappropriate rate is relatively small; and only when the port is pessimistic about the market or the channel competition is weak, sharing information may hurt the carrier who invested in information. Finally, the strength of the channel competition will enhance the impact of information inaccuracy on the maritime transport chain.


Comparative morphology and molecular phylogeny of Apicoporus n. Gen.: a new genus of marine benthic dinoflagellates formerly classified within Amphidinium.
The composition of the dinoflagellate genus Amphidinium is currently polyphyletic and includes several species in need of re-evaluation using modern morphological and phylogenetic methods. We investigated a broad range of uncultured morphotypes extracted from marine sediments in the Eastern Pacific Ocean that were similar in morphology to Amphidinium glabrum Hoppenrath and Okolodkov. To determine the number of distinct species associated with this phenotypic diversity, we collected LM, SEM, TEM and small subunit ribosomal DNA sequence information from different morphotypes, including the previously described A. glabrum. Both comparative morphological and molecular phylogenetic data supported the establishment of a new genus, Apicoporus n. gen., including at least two species, A. glaber n. comb., and A. parvidiaboli n. sp. Apicoporus is characterized by having amphiesmal pores and an apical pore covered by a hook-like protrusion; neither of these characters has been observed in other athecate dinoflagellates. The posterior end of Apicoporus parvidiaboli possessed varying degrees of "horn formation", ranging from slight to prominent. By contrast, the posterior end of Apicoporus glaber was distinctively rounded and lacked evidence of horn formation. Although these species were previously interpreted to be obligate heterotrophs, TEM and epifluorescence microscopy demonstrated that some cells of both species had unusually small but otherwise typical dinoflagellate plastids. The number and density of plastids in any particular cell varied significantly in the genus, but the plastids were almost always concentrated at the posterior end of the cells or around the nucleus. The presence of cryptic photosynthetic plastids in these benthic species suggests that photosynthesis might be much more widespread in dinoflagellates than is currently assumed.


Effect of Eu3+ doping on structural and optical properties of zirconium titanate.
The Europium activated (1-9 mol %) Zirconium Titanate nanoparticles (NPs) have been synthesized by the green solution combustion method using Aloe Vera gel extract as a reducing agent, followed by the calcination at 720 °C for 3hrs. All the synthesized samples crystallize in a pure orthorhombic crystal structure with the space group of Pbcn. The surface and bulk morphology were analyzed. The crystallite size increases, whereas the direct energy band gap was found to decrease with an increase in dopant concentration. Further, the effect of dopant concentration on the photoluminescence properties was studied. The presence of Eu3+ ion in the trivalent state in the host lattice was confirmed by its characteristic emission at 610 nm due to 5D0→7F2 (λex = 464 nm). The CIE coordinates were found in the red region of the CIE 1931 diagram. The CCT coordinates lie in the range 6288-7125 K. The Judd-Ofelt parameters and derived quantities were analyzed. This theory confirms the high symmetry of Eu3+ ions in the host lattice. These findings imply that ZTO:Eu3+ can be employed as a nanopowder material in a red-emitting phosphor material.


A gene homologous to plasminogen located on human chromosome 2q11-p11.
A plasminogen probe encoding kringles 1-3 detects homologous loci on human chromosomes 6 and 2 by somatic cell hybrid analysis. Regional localization by in situ hybridization places the loci at 6q26-27 and 2p11-q11. Further analysis by varying washing stringencies of hybridization filters reveals a greater homology with the chromosome 6 locus than with the chromosome 2 locus. These results confirm localization of the plasminogen gene to human chromosome 6q26-27 and indicate that a homologous sequence of unknown identity resides on chromosome 2p11-q11.


Usefulness of heavily T2-weighted magnetic resonance imaging in the diagnosis of alveolar lung metastases from pancreas mucinous adenocarcinoma.
We report the case of a patient with pancreatic adenocarcinoma and mucinous air-space metastases, in which the diagnosis was suspected at magnetic resonance using heavily T2-weighted images obtained with magnetic resonance hydrographic sequences.


Daratumumab, Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS.
In the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS. Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m2) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS). In total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified. In this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.


The effects of ω-6 and ω-3 fatty-acids on early stages of mice DMBA submandibular glands tumorigenesis.
The aim of this work was: to assess the impact of diets enriched in polyunsaturated fatty acids ω-3 and ω-6 families on the lipid profile of cell membrane and their effect on cycle regulation and apoptosis, evaluated by TP53 and Ki-67 expression in 9,10-dimethyl-1,2-benzanthracene (DMBA) induced tumor development in submandibular glands (SMG) in murine models. To generate tumorigenic changes, SMG mice in the experimental group were injected with 50μl of 0.5% of DMBA. Both control (no DMBA) and experimental groups of BALB/c mice were fed with: chia oil (ChO), rich in ω-3 fatty acid; corn oil (CO), rich in ω-6/ω-3 fatty acid; and safflower (SO) oil, rich in ω-6fatty acid. Results demonstrate novel differential effects of ω-3 and ω-6 PUFAs on the regulation of early tumorigenesis events in murine SMG injected with DMBA. This knowledge may help to develop chemoprotective treatments, therapeutic agents and health promotion and prevention activities in humans.


Isolation, culture, and verification of human sweat gland epithelial cells.
Human sweat gland epithelial cells (SGECs) have been isolated and grown in vitro, However, slow proliferation makes the culture of these cells extremely difficult. The present study was carried out to explore the modified culture medium for SGECs in vitro. Full-thickness skin samples were minced (1 mm(3)) and digested overnight with type II collagenase. The gland coils were removed under an inverted phase-contrast microscope. An adherent culture method was used to isolate and culture SGECs. Staining with hematoxylin and eosin was performed, followed by observation of the morphologic features of these cells. Immunofluorescence staining with antibodies to cytokeratins CK7, CK18, and CK19 and carcinoembryonic antigen (CEA) was performed to verify the presence of SGECs. Growth curves by MTT were created for cells grown in serum-free keratinocyte medium and in modified keratinocyte medium containing 2.5% fetal bovine serum (FBS). One week after culturing, the cells grew well and were polygonal or irregular in shape by inverted phase contrast microscopy. Cell fusion, with a characteristic paving-stone arrangement, reached 100% after approximately 3 weeks in culture. Immunofluorescence staining indicated expression of CK7, CK18, CK19, and CEA. Compared with SGECs grown in serum-free keratinocyte medium, the proliferation of SGECs grown in modified culture medium with low concentration of FBS at days 6, 9, and 12 was significantly accelerated (p < 0.05). This study suggests that keratinocyte medium supplemented with 2.5% FBS is effective and suitable for the culture of SGECs.


[Comparison of anatomy and imaging of the orbital area and the nasolacrimal duct].
The orbit and its appendages were analysed on anatomical sections, CT scans and magnetic resonance imaging in order to define the various constituents of the orbitonasolacrimal apparatus in the various planes. The series of sections presented should enable surgeons to define the landmarks in this region, especially in the approach to deep structures.


Progesterone (CIDR)-based timed AI protocols using GnRH, porcine LH or estradiol cypionate for dairy heifers: ovarian and endocrine responses and pregnancy rates.
The overall objective was to compare the efficacy of GnRH, porcine LH (pLH) and estradiol cypionate (ECP), in a modified Ovsynch/fixed-time AI (FTAI) protocol that included a controlled internal drug [progesterone] release (CIDR) device. In Experiment 1, heifers received a CIDR on Day -10, and PGF (25mg) on Day -3. At CIDR insertion, heifers received 100 microg of GnRH (n=6), 0.5mg of ECP (n=6), 5.0mg of pLH (n=6) or 2 mL of saline (n=7); these treatments were repeated on Day -1, except for ECP, that was repeated on Day -2, concurrent with CIDR-removal. The 5.0 mg pLH was the least effective with a longer interval to ovulation than the other groups combined (102 versus 64 h; P<0.05). Overall mean LH concentrations (1.6 ng/mL) and area under the curve (AUC) did not differ among treatments, but mean peak LH concentration was lower in heifers given 5 mg of pLH compared to all other groups (4.5 versus 10.3 ng/mL; P<0.05). In Experiment 2, heifers on CIDR-based Ovsynch protocols were given 12.5mg pLH (n=6; pLH-low), 25.0 mg pLH (n=6, pLH-high), or 100 microg GnRH (n=5; control). Heifers in the pLH-high group had greater (P<0.01) plasma LH concentrations (between 12 and 20 h) than GnRH-treated heifers, but the pLH treatments did not differ (P>0.10). Area under the curve for LH (ng/32 h) was at least 50% greater (P<0.01) in pLH-treated heifers compared to GnRH-treated heifers (mean, 41.3, 56.3 and 20.3 for pLH-low, pLH-high and GnRH, respectively). Ovulation occurred in 15 of 17 heifers. Progesterone concentrations were higher on Days 9 and 14 in heifers given 25mg of pLH, suggesting enhanced CL function. In Experiment 3, 240 heifers were assigned to CIDR-based Ovsynch/FTAI protocols. The first and second hormonal treatments (with an intervening PGF treatment on Day -3) were GnRH/GnRH (100 microg), ECP/ECP (0.5 mg), pLH/pLH (12.5 mg) or GnRH/ECP, respectively; pregnancy rates were 58.7, 66.1, 45.9 and 48.3%, respectively (ECP/ECP>both pLH/pLH and GnRH/ECP; P<or=0.05). In conclusion, CIDR-based Ovsynch/FTAI protocols using either GnRH/GnRH or ECP/ECP yielded pregnancy rates about 20% points higher than previously reported for dairy heifers bred to Ovsynch/FTAI in the absence of a CIDR.


Operational culture conditions determinate benzalkonium chloride resistance in L. monocytogenes-E. coli dual species biofilms.
Biofilms pose a serious challenge to the food industry. Higher resistance of biofilms to any external stimuli is a major hindrance for their eradication. In this study, we compared the growth dynamics and benzalkonium chloride (BAC) resistance of dual species Listeria monocytogenes-Escherichia coli 48 h biofilms formed on stainless steel (SS) coupons surfaces under batch and fed-batch cultures. Differences between both operational culture conditions were evaluated in terms of total viable adhered cells (TVAC) in the coupons during 48 h of the mixed-culture and of reduction of viable adhered cells (RVAC) obtained after BAC-treatment of a 48 h biofilm of L. monocytogenes-E. coli formed under both culture conditions. Additionally, epifluorescence microscopy (EFM) and confocal scanning microscopy (CLSM) permitted to visualize the 2D and 3D biofilms structure, respectively. Observed results showed an increase in the TVAC of both strains during biofilm development, being the number of E. coli adhered cells higher than L. monocytogenes in both experimental systems (p < 0.05). Additionally, the number of both strains were higher approximately 2.0 log CFU/coupon in batch conditions compared to fed-batch system (p < 0.05). On the contrary, significantly higher resistance to BAC was observed in biofilms formed under fed-batch conditions. Furthermore, in batch system both strains had a similar reduction level of approximately 2.0 log CFU/coupon, while significantly higher resistance of E. coli compared to L. monocytogenes (reduction level of 0.69 and 1.72 log CFU/coupon, respectively) (p < 0.05) was observed in fed-batch system. Microscopic image visualization corroborated these results and showed higher complexity of 2D and 3D structures in dual species biofilms formed in batch cultures. Overall, we can conclude that the complexity of the biofilm structure does not always imply higher resistance to external stimuli, and highlights the need to mimic industrial operational conditions in the experimental systems in order to better assess the risk associated to the presence of pathogenic bacterial biofilms.


A pilot study of Biotene OralBalance® gel for oral care in mechanically ventilated preterm neonates.
Neonatal ventilator-associated pneumonia (VAP) is associated with increased morbidity and mortality. In adults on mechanical ventilation, timed oral care decreases the frequency of VAP, but this approach has not been studied in neonates. To evaluate the feasibility of a randomized trial of timed oral care with Biotene OralBalance® gel and estimate the required sample size for such a trial. Infants were eligible for enrollment if they were born before 28 weeks of gestation, and were mechanically ventilated between 7 and 10 postnatal days. Infants were randomized to receive timed oral care with Biotene OralBalance® gel or sterile water. All subjects were treated with a standard bundle of procedures to reduce the risk of VAP. We enrolled 41 of 46 eligible infants (89%). Compliance with timed oral care protocol was 97%. No local oral side effects of Biotene OralBalance® gel were observed. There were no significant group differences in mortality or short-term outcomes, except length of hospital stay which was significantly shorter in the Sterile water group (p = 0.02). A lower rate of VAP was found in the Biotene group, although the difference was not statistically significant (9/1000 ventilator-days versus 17/1000 ventilator-days in the Sterile water group, respectively; p = 0.16). The results of this pilot study support the feasibility of a randomized trial of timed oral care with Biotene OralBalance® gel for prevention of VAP in mechanically ventilated neonates.


Relation of cytolytic activity of an ether-deoxy lysophosphatidylcholine analog to available membrane surface. Comparison of normal and tumor cells from mice.
1-Hexadecylpropanediol-3-phosphorylcholine, an ether-deoxy analog of lysophosphatidylcholine, has been employed to study the sensitivity of various types of mouse cells with respect to changes in membrane permeability induced by lysophosphatidylcholine. Cells used included erythrocytes, thymocytes, spleen cells and macrophage, as well as 4 different tumors (2 lymphomas, 1 Ehrlich acites and 1 methylcholanthren-induced fibrosarcoma). The sensitivity to the lysophosphatide (on a per-cell basis) of the above cell types varied by a factor of 65. When lytic concentrations were related to available membrane surface, this variation was reduced to a factor of 2.5. No principal difference was observed between the sensitivity of normal versus tumor cell membranes with respect to lysophosphatidylcholine lysis. Membrane surface, available for lysophosphatidylcholine, has been estimated from binding equilibria of 14C-labelled deoxy-lysophosphatidylcholine to the cells under standardized conditions. This method is based on the finding that binding equilibria of lysophospholipids to cells are predominantly determined by the available membrane surface.


Protection of chickens from lethal influenza infection by vaccinia-expressed hemagglutinin.
To study the immune response of the chicken to specific influenza proteins, we have constructed a recombinant vaccinia virus containing the hemagglutinin gene of influenza A/Turkey/Ireland/1378/83 (H5N8). In mammalian cell culture the hemagglutinin expressed by this recombinant virus was full-length, cleaved into HA1 and HA2 in the absence of trypsin, and transported to the cell surface, confirming that other virus products are not required for cleavage activation. Chickens inoculated through the wing web with the live recombinant virus produced extremely low levels of hemagglutination-inhibiting or infectivity-neutralizing antibody. However, they were protected from lethal H5 influenza virus challenge. Protection extended to the antigenically distinct virulent H5 viruses, Chicken/Pennsylvania/1370/83 and Chicken/Scotland/59. Chemically bursectomized vaccinated chickens were not protected, whereas normal chickens with very low antibody levels (less than 10) obtained by passive transfer were protected in a dose-dependent fashion. This indicates that despite the low antibody titers induced by vaccination, protection was mediated by antibody.


Repair of radiation-induced DNA double-strand breaks in human fibroblasts is consistent with a continuous spectrum of repair probability.
To propose a novel interpretation of DNA double-strand break (dsb) repair based on the distribution of energy micro-deposition. Double-strand break repair curves were studied either after irradiation at 4 degrees C or at 37 degrees C (low dose rate). Two human fibroblast cell lines were used: a control line, HF19, and an ataxia telangiectasia repair-deficient line, AT5BI. Irradiations were made with gamma-rays or alpha-particles (241Am). Repair data were fitted by the variable repair half-time (VRHT) model. Assuming that each dsb has its own inherent repair half-time (IRHT) and that the VRHT is the average of the IRHT at any time during repair, the distribution of the IRHT was calculated. At the end of the irradiation, the distribution was a continuous asymmetric curve with a maximum of dsb having a short IRHT. After 1 h of repair, the curve became bell-shaped. There is a striking similarity between the distribution of dsb repair half-times and that of energy micro-deposition described by Goodhead et al. (1993). This similarity suggests a possible causal relationship between the energy density deposition and the repair rate or the probability of dsb repair.


Subcutaneous emphysema and pneumomediastinum following cocaine inhalation: a case report.
Subcutaneous emphysema or pneumomediastinum can occur as a complication of illicit drug use although this is rare. When occurring without a pneumothorax and spontaneously, it is usually treated conservatively, but can have serious consequences. Here, we present the case of an otherwise healthy 23-year-old Caucasian man who presented to the Emergency Department at our institution and was found to have both subcutaneous emphysema and pneumomediastinum as a result of cocaine use. His only presenting symptom was mild chest pain and he had palpable subcutaneous crepitations. He underwent a series of investigations including a chest radiograph and computed tomography as well as a barium fluoroscopy study to rule out secondary pneumomediastinum, which can be fatal. There were no other pulmonary features of illicit drug use, such as granulomas or fibrosis, seen on radiological imaging. He was subsequently managed with a period of observation and supportive care. We report a rare case of subcutaneous emphysema and pneumomediastinum likely due to the nasal insufflation of cocaine. We discuss the necessary investigations to rule out any serious underlying pathology. These should be considered in patients who present with chest pain after cocaine use.


Elevated Metabolic Activity on 18F-FDG PET/CT Is Associated with the Expression of EZH2 in Non-small Cell Lung Cancer.
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in the pathogenesis of lung cancer. We evaluated the metabolic characteristics of non-small cell lung cancer (NSCLC) in patients with and without expression of EZH2 using 18F-fluorodeoxyglucose positron-emission tomography/ computed tomography (18F-FDG PET/CT). The EZH2 protein expression of 268 patients with resected NSCLC, whose preoperative 18F-FDG PET/CT information was available, was evaluated by immunohistochemistry with clone 6A10 antibody; cases with Allred score ≥3 were considered positive. Maximized standard uptake values in cases of EZH2-positive NSCLC and adenocarcinoma were significantly higher in comparison to EZH2-negative cases (p<0.001, and p<0.001, respectively). The expression of EZH2 in NSCLC and adenocarcinoma was associated with significantly poorer survival. In patients with NSCLC and adenocarcinoma, EZH2 positivity was associated with a high uptake of FDG, suggesting that EZH2 might define metabolically malignant lung cancer.


Chromosome analyses in man in the course of chemoprophylaxis against tuberculosis and of antituberculosis chemotherapy with isoniazid.
Cytogenetic analyses were carried out in lymphocytes of 37 persons before and during a primary chemoprophylaxis or a preventive chemotherapy with isoniazid as well as of 30 patients suffering from active pulmonary tuberculosis before and during a chemotherapy with isoniazid in combination with two other antimycobacterial drugs. The results of the four participating research groups consistently reveal no indication for a chromosome damaging activity of isoniazid, of its metabolites in the human organism and of the administered drug regimens.


The WRIST series--what have we learnt?
The evolution of the WRIST (Washington Radiation for In-Stent Restenosis Trial) series has reflected the progress that has been made in intracoronary radiation for In-stent restenosis of coronary artery and saphenous vein graft disease. We have enrolled over 1,500 patients in eleven WRIST series performed at the Washington Hospital Center, providing a unique and powerful data set that is pivotal in our understanding of vascular brachytherapy. This review is intended to give an overview of the individual trials, summarize pertinent lessons that have been learned and give insight into future of intracoronary radiation.


Restless Legs Syndrome and Severe Preeclampsia: A Case-Control Study.
This study sought to determine whether there is an association between restless legs syndrome (RLS) and severe preeclampsia using a case-control study design. A total of 147 patients with severe preeclampsia and 147 patients with normal pregnancies were evaluated for symptoms of RLS. In the first phase, before or immediately after delivery, participants were given a questionnaire on common complaints experienced during pregnancy. Mixed with these complaints were the symptoms that comprised the diagnostic criteria for RLS. If a participant indicated she met the diagnositic criteria, she was informed about RLS. In the second phase, a severity evaluation was performed in this population using the International Restless Legs Syndrome Study Group Rating Scale. Among the participants, independent of the presence of preeclampsia, 13.61% met the criteria for a diagnosis of RLS. There was no statistical difference between groups (severe preeclampsia: 12.93% vs. controls: 14.29%; odds ratio [OR] 0.89; 95% CI 0.46-1.74, P = 0.37). After analysis, 65% of patients with RLS had a score on the International Restless Legs Syndrome Study Group Rating Scale compatible with "very severe" or "severe" RLS. There was again no statistical difference between groups for the combination of "severe" and "very severe" scoring criteria (severe preeclampsia: 68.42% vs. controls: 61.90%; OR 1.33; 95% CI 0.36-4.93, P = 0.66) and "very severe" alone (severe preeclampsia: 21.05% vs. controls: 4.76%; OR 5.33; 95% CI 0.54-52.73, P = 0.11). The prevalence of RLS among pregnant women in our study was in accordance with the medical literature and avoided the probable bias caused by the high number of other symptoms experienced during pregnancy. There were no significant differences between normotensive participants and those with severe preeclampsia. In general, symptom severity was high, with a tendency toward greater severity in patients with severe preeclampsia, but this difference did not reach statistical significance.


Characterization and comparison of virulent bacteriophages of Streptococcus thermophilus isolated from yogurt.
Seven virulent bacteriophages of Streptococcus thermophilus were characterized at the molecular level and classified into 2 subgroups (A and B) by DNA/DNA hybridization experiments and analysis of their structural proteins. Two representatives of subgroups A and B were compared to 3 representatives of Neve's subgroups I, II and III (Neve et al, 1989) by Southern blot experiments. These isometric-headed phages possess a double-stranded DNA genome varying between 30-44 kilobase (kb) pairs. Subgroup A is composed of 3 phages (phi 57 as representative) with similar structural proteins as determined by sodium dodecyl sulfate-poly-acrylamide gel (SDS-PAGE) electrophoresis (estimated molecular weights of 31,000 and 27,500 for phage phi 57 and 32,000 and 27,000 for the 2 others). A common structural protein of 43,000 was found for phages of subgroup B. Phages phi 57 (subgroup A) and a10/J9 or PO (Neve's subgroups I or II, respectively) belonged to the same subgroup as determined by DNA/DNA hybridization experiments. Partial DNA homology was detected among all the phages tested except for phage phi ST27 of AW Jarvis. Phage-host interactions were also investigated by cross-propagation of the 7 studied phages on different indicator strains. A complete lack of correlation existed between the DNA homology grouping of the phages and their host range. Various restriction-modification systems were detected in some of the Streptococcus thermophilus strains.


Ranibizumab for the treatment of wet AMD: a summary of real-world studies.
Data from real-world studies of ranibizumab in neovascular (wet) age-related macular degeneration suggest that outcomes in clinical practice fail to match those seen in clinical trials. These real-world studies follow treatment regimens that differ from the fixed dosing used in the pivotal clinical trial programme. To better understand the effectiveness of ranibizumab in clinical practice, we conducted a comprehensive evaluation of 12-month outcomes reported in peer-reviewed 'real-world' publications. Key measures included in our analysis were mean change in visual acuity (VA) and the proportion of patients gaining ≥15 letters or losing ≤15 letters. Twenty studies were eligible for inclusion in our study, with 18 358 eyes having sufficient data for analysis of 12-month outcomes. Mean baseline VA ranged from 48.8 to 61.6 Early Treatment Diabetic Retinopathy Study letters. Mean change in VA was between -2.0 and +5.5 letters, with a grand mean of +2.9±3.2, and a weighted mean (adjusted for the number of eyes in the study) of +1.95. Eleven studies reported that 19±7.5 (mean value) of patients gained ≥15 letters, while in 12 studies the mean percentage of patient losing ≤15 letters was 89±6.5%. Our comprehensive analysis of real-world ranibizumab study data confirm that patient outcomes are considerably poorer than those reported in randomised control trials of both fixed and pro re nata regimens.


Heterochromatin as an incubator for pathology and treatment non-response: implication for neuropsychiatric illness.
Heterochromatin is a higher order assembly that is characterized by a genome-wide distribution, gene-repression, durability and potential to spread. In this light, it is an appealing mechanism to interpret the neurobiology of complex brain disorders such as schizophrenia where downregulation of expression appears to be the norm. H3K9 methylation (H3K9me) can initiate the seeding of a heterochromatin assembly on an inactive or poorly coordinated promoter as a consequence of a decline in transactivators either from disuse or from misuse. H3K9me can extend its influence by spatial spreading through the mechanism of recursively recruiting adapters, such as heterochromatin protein 1 (HP1) homodimers. HP1 itself serves as a platform for other repressive proteins such as DNA methyltransferases. In full color, heterochromatin can occupy genome-wide gene networks, tissue specific ontologies and even rearrange the nuclear architecture. Heterochromatin in the brain is modified by small molecule pharmacology and serves a physiological role in the functioning of dopamine neurons and the construction of memory. From a therapeutic perspective, the durable nature of heterochromatin implies that it may require disassembly before the full genomic-potential of standard pharmacotherapies is achieved, especially in treatment resistant patients.


Tyrosine kinase inhibitors. 5. Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]- and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor.
A series of 4-substituted quinazolines and related compounds have been prepared and evaluated for their ability to inhibit the tyrosine kinase activity of the epidermal growth factor receptor on a phospholipase C-gamma 1-derived substrate. The results show a narrow structure-activity relationship (SAR) for the basic ring system, with quinazoline being the preferred chromophore and benzylamino and anilino the preferred side chains. In the 4-anilino series, substitution on the 3-position of the phenyl ring with small lipophilic electron-withdrawing groups provided analogues with enhanced potency. Two series of compounds [4-(phenylmethyl)amino and 4-(3-bromophenyl)amino] were studied to determine SARs for quinazoline substituents. In the more active 4-(3-bromophenyl)amino series, electron-donating groups (NH2, OMe) at the 6- or 7-position increased activity, in a pattern consistent with a requirement for high electron density in the vicinity of the 8-position of the quinazoline ring. The 6,7-dimethoxy derivatives were the most effective in both series, with the 4-(3-bromophenyl)amino derivative (3) having an IC50 of 0.029 nM, making it by far the most potent reported inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor enzyme.


Activin A stimulates meiotic maturation of human oocytes and modulates granulosa cell steroidogenesis in vitro.
To test the hypothesis that activin A promotes in vitro human oocyte meiotic maturation while inhibiting steroid secretion by nonluteinized antral granulosa cells. Prospective randomized controlled study. A university medical center. Nine women ranging in age from 31-44 years who were undergoing oophorectomy for nonovarian pathology. Analysis of meiotic maturation of oocytes and steroid secretion by granulosa cells cultured in the presence or absence of activin A. Germinal vesicle breakdown (GVBD) and attainment of metaphase II (MII) in oocytes, and progesterone and E2 secretion by granulosa cells. Activin A significantly enhanced GVBD (91% vs. 65%) for control and maturation to MII (56% vs. 35% for control) of immature oocytes. Activin A significantly suppressed basal, and inhibin A-and FSH-stimulated progesterone and E2 secretion by nonluteinized granulosa cells. Activin A is a promoter of oocyte maturation in vitro and a modulator of granulosa cell steroidogenesis in culture.


Quartz fibers as templates for biopolymers.
The polymerization of silica in water solution to form quartz fibers proceeds by a dehydration process, analogous to condensation polymerization in organic high-polymers, in which monomeric Si(OH)4 groups unite through Si--O--Si bonds with the elimination of H2O. The resulting fibers are structurally polar along the direction of elongation, are enantiomorphous, and generally show stereospecific twisting around the direction of elongation. In these regards the fibers are analogues of biopolymers such as RNA and DNA. Quartz also possesses specific adsorptive relations to a wide range of organic substances including monomer amino acids, short-chain polypeptides, and proteins. These involve hydrogen-bonding between (OH) or silanol groups on the surface of the quartz with active side-groups on the organic molecules, and in part are epitaxial through dimensional coincidences in the interface. Geochemical evidence indicates that quartz was deposited in the early Precambrian ocean either by direct crystallization from seawater or by recrystallization of amorphous silica. What is of interest is the possible role of quartz fibers as a template and co-polymer in the passage of biomonomers in the pre-biotic ocean to the long-chain biopolymers such as nucleic acids and proteins that are involved in life processes.