Association between fibromyalgia and psychiatric disorders in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease that may affect many organs, with musculoskeletal symptoms being the most common. Fibromyalgia (FM) is frequent in SLE patients. Psychiatric disorders such as anxiety and depression are also present in many SLE patients. The aim of our study is to determine the relationship between FM and psychiatric symptoms (PS), both anxious (AS) and depressive (DS), and its impact on health status in SLE patients. In a total of 84 SLE patients we studied the presence of both FM and PS using specific questionnaires (Hamilton). We also evaluated health status and SLE disease activity by both the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and serological markers. Patients performed the Short Form 12 (SF-12) questionnaire as a quality of life measure. Qualitative variables were compared using Pearson's chi-square test and Fisher's exact test, and Student's t-test was used for quantitative variables. The Mann-Whitney U-test was applied if a normal distribution was not observed. Thirty patients were diagnosed with FM (35.7%), 16 had clinical signs DS (19%) and 30 had clinical signs AS (35.7%). We found a statistically significant association between FM and AS (p<0.001), and between FM and DS (p<0.001). Higher SF-12 physical component and mental component scores were observed in FM group compared to non-FM group (p<0.001). We have not found any associations between SLE activity and FM and PS. There is a high prevalence of FM in SLE patients, and a strong association with DS and AS. FM contributes to worsening health status in SLE patients. SLE activity has little or no impact either on psychiatric symptoms or FM.


A randomized trial comparing wireless capsule endoscopy with push enteroscopy for the detection of small-bowel lesions.
Wireless capsule endoscopy is a new, painless method of imaging the entire small bowel. It has not been compared with push enteroscopy. We compared the sensitivity, specificity, and safety of capsule and push enteroscopy in detecting small-bowel lesions. Nine to 13 radiopaque, colored beads (3-6 mm diameter) were sewn in random order inside 9 canine small bowels, half within the first meter, and confirmed on x-ray. After recovery, the number, order, and color of beads were assessed in 23 capsule enteroscopies and 9 push enteroscopies in a random order. The surgeons, push enteroscopists, capsule video interpreters, and pathologist were blinded to the others' findings. The capsules identified more beads than push enteroscopy (median, 6 [range, 2-9] vs. 3 [range, 2-6 beads]; P < 0.001). The sensitivity of the capsule was 64% compared with 37% for push enteroscopy. The specificity was 92% for capsule enteroscopy and 97% for push enteroscopy. The capsules identified significantly more beads beyond the reach of the push enteroscope (median, 4 [range, 2-7] vs. 0; P < 0.0001). Hair, ingested plastic, ulceration, submucosal swelling, and worms were clearly identified by the capsule. The capsules passed safely through the animals with no significant histologic findings. Wireless capsule endoscopy detected more abnormalities in the small bowel than push enteroscopy.


Identification of new 4-N-substituted 6-aryl-7H-pyrrolo[2,3-d]pyrimidine-4-amines as highly potent EGFR-TK inhibitors with Src-family activity.
The epidermal growth factor receptor is an important target in molecular cancer therapy. Herein, the enzymatic inhibition potential of a series of chiral and non chiral pyrrolopyrimidine based derivatives have been investigated and optimised. Overall, seven new compounds were identified having enzymatic IC50 values comparable to or better than the commercial drug Erlotinib. High activity was also confirmed towards the epidermal growth factor receptor L858R and L861Q mutants. Based on calculated druglike properties, eight compounds were further evaluated towards a panel of 52 other kinases revealing interesting Src-family kinase and colony stimulating factor 1 receptor kinase inhibitory activity. Cell proliferation studies with the cell lines A431, C-33A, AU-565, K-562 and genetically engineered Ba/F3-EGFR(L858R) cells also showed several molecules to be more active than Erlotinib, and thus confirming these pyrrolopyrimidines as attractive drug candidates or lead structures.


A pathobiologic pathway linking thrombopoietin, GATA-1, and TGF-beta1 in the development of myelofibrosis.
Idiopathic myelofibrosis (IM) is a disease characterized by marrow fibrosis, abnormal stem/progenitor cell trafficking, and extramedullary hematopoiesis frequently associated with alterations in megakaryocytes (Mks). Mice harboring genetic alterations in either the extrinsic (ectopic thrombopoietin expression, TPO(high) mice) or intrinsic (hypomorphic GATA-1 mutation, GATA-1(low) mice) control of Mk differentiation develop myelofibrosis, a syndrome similar to IM. The relationship, if any, between the pathobiologic mechanism leading to the development of myelofibrosis in the 2 animal models is not understood. Here we show that plasma from GATA-1(low) mice contained normal levels of TPO. On the other hand, Mks from TPO-treated wild-type animals (TPO(high) mice), as those from GATA-1(low) animals, had similar morphologic abnormalities and contained low GATA-1. In both animal models, development of myelofibrosis was associated with high transforming growth factor beta1 (TGF-beta1) content in extracellular fluids of marrow and spleen. Surprisingly, TPO treatment of GATA-1(low) mice restored the GATA-1 content in Mks and halted both defective thrombocytopoiesis and fibrosis. These data indicate that the TPO(high) and GATA-1(low) alterations are linked in an upstream-downstream relationship along a pathobiologic pathway leading to development of myelofibrosis in mice and, possibly, of IM in humans.


An improved method for the derivation of high quality iPSCs in the absence of c-Myc.
Induced pluripotent stem cells (iPSCs) hold tremendous potential for the development of new regenerative medicine therapies and the study of molecular mechanisms of pluripotency and development. However, reactivation of c-Myc, which results in tumor formation in chimeric mice, is a major roadblock in the translation of iPSCs into therapies. Although ectopic expression of c-Myc is not absolutely required for somatic reprogramming, in the absence of c-Myc, the overall efficiency of reprogramming is drastically reduced and the reprogramming time is increased. Subtle, abnormal epigenetic modifications in iPSCs derived in the absence of c-Myc have also been documented. Therefore, we developed a reprogramming method without c-Myc to generate high-quality iPSCs, a prerequisite to harnessing the full potential of iPSCs. In this study, we determined that serum replacement (SR)-based culture conditions dramatically increased the transcription factor-mediated reprogramming of mouse embryonic fibroblast cells (MEFs). The process was shortened to approximately 8 days when Oct4/Sox2/Klf4 (3F)-transduced MEFs were first cultured for 3 days under low serum conditions (LS protocol). The 3F-derived iPSCs that were generated by this method resembled mouse ES cells (mESCs) in morphology, gene expression, and in vitro differentiation. Finally, we observed that 3F-derived iPSC colonies were able to reach definite pluripotency in terms of molecular signatures when the catalytic function of c-Myc was tolerated. The 3F induction of pluripotency described here should facilitate the use of iPSCs and may also facilitate the mechanistic dissection of somatic reprogramming.


Ultrasonic emulsification of eucalyptus oil nanoemulsion: antibacterial activity against Staphylococcus aureus and wound healing activity in Wistar rats.
The plant derived essential oil nanoemulsion was prepared using a mixture of components containing eucalyptus oil as organic phase, water as continuous phase, and non ionic surfactant, Tween 80, as emulsifier at a particular proportion of 1:1 v/v%. The ultrasonication was applied for varied processing time from 0 to 30 min to study the effect of time on the formation of nanoemulsion and physical stability of formulation by this method. The transparency and stability of emulsion was enhanced when the sonication time was increased compared to hand blender emulsion. The most stable nanoemulsion was obtained in 30 min sonication having the mean droplet diameter of 3.8 nm. The antibacterial studies of nanoemulsion against Staphylococcus aureus by time kill analysis showed complete loss of viability within 15 min of interaction. Observations from scanning electron microscopy of treated bacterial cells confirmed the membrane damage compared to control bacteria. Furthermore, the wound healing potential and skin irritation activity of the formulated nanoemulsion in Wistar rats, suggested non-irritant and higher wound contraction rate with respect to control and neomycin treated rats. These results proposed that the formulated system could be favourable for topical application in pharmaceutical industries.


Executive Summary: Transforming Moral Distress into Moral Resilience in Nursing.
To examine practices for addressing moral distress, a collaborative project was developed by the Johns Hopkins Berman Institute of Bioethics, the Johns Hopkins School of Nursing, the American Journal of Nursing, and the Journal of Christian Nursing, along with the American Association of Critical-Care Nurses and the American Nurses Association. Its purpose was to identify strategies that individuals and systems can use to mitigate the detrimental effects of moral distress and foster moral resilience. On August 11 and 12, 2016, an invitational symposium, State of the Science: Transforming Moral Distress into Moral Resilience in Nursing, was held at the Johns Hopkins School of Nursing in Baltimore, Maryland. Forty-five nurse clinicians, researchers, ethicists, organization representatives, and other stakeholders took part. The result of the symposium was group consensus on recommendations for addressing moral distress and building moral resilience in four areas: practice, education, research, and policy. Participants and the organizations represented were energized and committed to moving this agenda forward. The full report is available online at http://journals.lww.com/ajnonline/Pages/Moral-Distress-Supplement.aspx.


Hybrid transfer RNA genes in phage T4.
We describe the isolation and characterization of two unusual amber suppressor forms of T4 tRNALeu. The sequences of the suppressor tRNAs can be described as hybrids of wild-type tRNALeu and suppressor tRNAGln molecules: the chain lengths and majority of the nucleotide residues corresponded to tRNALeu, but CUA anticodons flanked by 2-14 residues were identical to tRNAGln. The uncertainty as to the exact number of flanking residues correlated with tRNAGln is due to the similarity of the two tRNA sequences in this region. No evidence was found for changes in other T4 tRNAs. We propose that genes for the hybrid tRNAs were produced by mispairing of DNAs at anticodon segments of tRNALeu and tRNAGln with a double crossover flanking those segments.


Determining time-weighted average concentrations of nitrate and ammonium in freshwaters using DGT with ion exchange membrane-based binding layers.
Commercially-available AMI-7001 anion exchange and CMI-7000 cation exchange membranes were utilised as binding layers for DGT measurements of NO3-N and NH4-N in freshwaters. These ion exchange membranes are easier to prepare and handle than DGT binding layers consisting of hydrogels cast with ion exchange resins. The membranes showed good uptake and elution efficiencies for both NO3-N and NH4-N. The membrane-based DGTs are suitable for pH 3.5-8.5 and ionic strength ranges (0.0001-0.014 and 0.0003-0.012 mol L-1 as NaCl for the AMI-7001 and CMI-7000 membrane, respectively) typical of most natural freshwaters. The binding membranes had high intrinsic binding capacities for NO3-N and NH4-N of 911 ± 88 μg and 3512 ± 51 μg, respectively. Interferences from the major competing ions for membrane-based DGTs are similar to DGTs employing resin-based binding layers but with slightly different selectivity. This different selectivity means that the two DGT types can be used in different types of freshwaters. The laboratory and field experiments demonstrated that AMI-DGT and CMI-DGT can be an alternative to A520E-DGT and PrCH-DGT for measuring NO3-N and NH4-N, respectively, as (i) membrane-based DGT have a consistent composition, (ii) avoid the use of toxic chemicals, (iii) provided highly representative results (CDGT : CSOLN between 0.81 and 1.3), and (iv) agreed with resin-based DGTs to within 85-120%.


Augmentation of coronary responsiveness to serotonin at the site of X-ray-induced intimal thickening in miniature pigs.
X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs. In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber. The percent reduction in coronary diameter evoked with 10 micrograms.kg-1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M[ [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 micrograms.kg-1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2[52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) microns] than at the denuded sites without X-irradiation [group 2, 58(5) microns] (P < 0.05). These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle.


Novel neurotrophic effects of sphingosylphosphorylcholine in cerebellar granule neurons and in PC12 cells.
Sphingosylphosphorylcholine (SPC) is a choline-containing naturally occurring derivative of sphingolipid involved in various biological processes. Here we show that SPC displays neurotrophic effects in cerebellar granule neurons (CGNs) and in PC12 cells. When CGNs were cultured under non-depolarizing condition, they exhibited condensed and fragmented nuclei typical of apoptotic phenotype. SPC added to the culture medium rescued cells from undergoing apoptosis. The anti-apoptotic effect of SPC was dependent on the presence of extracellular Ca2+, suggesting that Ca2+ influx occurs upon SPC treatment. In PC12 cells, SPC displayed nerve growth factor-like neuritogenic effect which was sensitive to the presence of Ca2+ channel blocker and Ca2+ withdrawal from the medium. These results suggest that SPC plays novel neurotrophic effects in the nervous system.


The association of blood pressure with cancer incidence in a prospective study.
A cohort of 8,006 Japanese-American men living in Hawaii was examined from 1965 to 1968 and followed for about 20 years. The study identified 1,155 incident cases of histologically confirmed cancer and 648 deaths due to cancer. There was no association between systolic or diastolic blood pressure and total cancer incidence or deaths due to cancer. The relative risk was 1.03 for cancer incidence and 1.00 for cancer mortality for subjects with a systolic pressure of 160 mmHg or greater. Adjustment was made for age, smoking, alcohol, and measures related to obesity. When cancers of specified sites were studied, blood pressure was positively associated with the incidence of kidney cancer (17 cases). After adjustment for the significant effect of taking antihypertensive medication, the effect of blood pressure became nonsignificant. Among seven other cancer sites, there were no statistically significant associations with blood pressure after adjustment for confounding factors.


[Pharmacokinetics of cefpiramide concentration in lung tissues].
Concentrations of cefpiramide (CPM) in human lung tissues were determined after 1 g intravenous bolus injection in 6 patients with lung tumors and pyothorax. Concentrations of the CPM in blood and lung tissues were determined and analyzed pharmacokinetically. Levels of CPM in the lung tissues reached 38.4 micrograms/g at 2 hours and declined to 27.7 micrograms/g in 6 hours. Levels of CPM in the lung tissues were higher than 50% of those in the serum between 100 minutes and 360 minutes after the administration of CPM.


Acute lymphocytic leukemia after fulminant varicella associated with severe neutropenia.
Acute lymphocytic leukemia developed within 3 weeks after a fulminant case of varicella complicated by pneumococcal sepsis and severe bone marrow suppression in a child treated with filgrastim (human granulocyte colony-stimulating factor).


Myringoplasty Outcomes From the Swedish National Quality Registry.
Data from patients registered for myringoplasty during 2002 to 2012 in the Swedish National Quality Registry for Myringoplasty. Both conventional myringoplasty and fat-graft techniques were used aimed at healing the tympanic membrane in noninfected ears. Analysis was performed on data in a national database collected from 32 ear, nose, and throat clinics. Surgical procedures and outcomes, and patient satisfaction from a questionnaire were studied. The database was comprised of 3,775 surgical procedures, with follow-up available for analysis. One-third were children under the age of 15 years. The most common indication for surgery was infection prophylaxis. The overall healing rate of the tympanic membrane after surgery was 88.5%, with a high mean patient satisfaction. Complications registered were postoperative infection, tinnitus, or taste disturbance that occurred in 5.8% of patients. Swedish results for a large number of patients who completed myringoplasty are presented. The success rate in this study is comparable to other studies, and good patient-reported outcome measures of myringoplasty are presented. Databases for surgical procedures and clinical audits are systematic processes for continuous learning in healthcare. This study shows that clinical databases can be utilized to analyze national results of surgical procedures. 2b Laryngoscope, 127:2389-2395, 2017.


Leg muscle activation patterns of sit-to-stand movement in stroke patients.
To describe the characteristics of leg muscle activation patterns in hemiplegic stroke patients during the movement of rising from a chair and to determine the differences of leg muscle activation patterns between stroke fallers and nonfallers. Subjects stood up from an armless chair at a comfortable, self-paced speed. Leg muscle activation time and patterns during the sit-to-stand movement were analyzed using multichannel surface electromyography and a force platform. The differences between stroke fallers and nonfallers were compared. The mean onset time of muscle activity in the affected limbs of stroke fallers was markedly delayed for the tibialis anterior muscle and earlier for the soleus muscle. The muscle activation patterns in the affected side of the stroke fallers exhibited a wide range of variation. Seventy percent of our stroke fallers exhibited no or merely low-amplitude activity in their tibialis anterior muscle when the patients were rising from a chair. Half of the stroke fallers exhibited premature or excessive activation of their soleus muscle when the rising activity was initiated. Stroke patients who exhibited no or low-amplitude muscle activity in the tibialis anterior, associated with premature or excessive activation of the soleus muscle in their hemiplegic limbs, when rising from a chair were prone to falling. The compensatory excessive tibialis anterior and quadriceps muscle activation in the unaffected limbs of stroke patients might have a role in preventing them from falling.


Vascular disease burden and in-hospital outcomes among patients undergoing percutaneous coronary intervention in New York State.
The presence of atherosclerosis in extracardiac vascular beds is associated with an increased risk of adverse cardiovascular outcomes among stable patients with coronary artery disease (CAD). However, there is little data regarding the impact of the presence and extent of vascular disease on outcomes in patients with CAD undergoing percutaneous coronary intervention. We analyzed 69,045 consecutive patients from the New York State Coronary Angioplasty Reporting System database who underwent percutaneous coronary intervention between 1998 and 1999. Vascular disease burden was assessed by history of aortoiliac, femoral-popliteal, and carotid disease. Patients were stratified into 3 groups: CAD alone, CAD and 1 additional site, and CAD and 2 or 3 additional sites. A logistic regression model was constructed to determine the relation between vascular disease burden and in-hospital mortality. Any history of vascular disease was present in 5915 (8.6%) of the population, of whom 4840 (82%) had CAD and 1 other disease location and 1075 (18%) had CAD and 2 or 3 other disease locations. There was a significant relationship between the number of disease locations and hospital mortality, ranging from 0.7% in patients with CAD alone to 2.0% and 2.6% for patients with 1 or >or =2 disease locations, respectively (P<0.001). In unadjusted analysis, in-hospital mortality was approximately 3-fold higher (odds ratio, 2.89; 95% CI, 2.31 to 3.60; P<0.001) and 4-fold higher (odds ratio, 3.78; 95% CI, 2.57 to 5.56; P<0.001) for inpatients with CAD and additional vascular disease at 1 site and > or =2 sites, respectively. After multivariable adjustment, each additional vascular bed affected was associated with a 50% increase in in-hospital mortality (odds ratio, 1.50; 95% CI, 1.27 to 1.78; P<0.001). Among patients with CAD undergoing percutaneous coronary intervention, vascular disease burden is associated with higher rates of adverse events and is an independent predictor of in-hospital mortality.


Human high denisty apolipoprotein A-I-lysolecithin-lecithin and sphingomyelin complexes. A method for high yield recombinations to lipoprotein complexes of reproducible stoichiometry.
High denisty apolipoprotein A-1 (apoLp A-I) has been prepared in a chromatographically and immunochemically homogeneous form. This apoprotein forms trimeric and tetrameric aggregates in aqueous solutions at higher concentrations. ApoLp A-I has been recombined in almost quantitative yield in the presence of lysolecithin with phosphatidylcholine and sphingomyelin to particles of reproducible stoichiometry. Lysolecithin is not required for the interactions of lecithin and sphingomyelin with the apoprotein A-I or for the stability of these complexes. Dialysis removes most of the lysolecithin without the loss of lecithin and sphingomyelin. ApoLp A-I-lecithin particles have a molecular weight of 200 000 and contain 50 molecules lecithin and 25 of lysolecithin. ApoLp A-I-sphingomyelin complexes contain 50 sphingomyelin and 13 lysolecithin molecules. The former particles show up as discs of 100 A diameter, and the latter particles are 250 A in diameter. Their thickness was estimated as 25 A in the apoLp A-I lecithin and 60 A in the apoLp A-I-sphingomyelin particles. ApoLp A-I and lysolecithin form complexes whose densities depend on the lysolecithin concentration. Lysolecithin enhances the binding of phosphatidylcholine to apoLP A-I, yielding lipoprotein complexes with decreasing density. The yield of apoLp A-I-sphingomyelin-lysolecithin complexes is proportional to the lysolecithin concentration. The ratio of apoLp A-I to sphingomyelin in all these complexes remains constant.


Prospective randomized trial comparing a nitinol self-expanding coronary stent with low-pressure dilatation and a high-pressure balloon expandable bare metal stent.
The recent SCORES trial demonstrated that lower dilatation pressures seen with self-expanding (SE) stents may be associated with lower rates of target lesion revascularization (TLR). To determine whether SE stents with low-pressure dilatation are as safe and effective as balloon expandable (BE) stents. We randomly assigned 254 patients with 279 coronary lesions to groups receiving either SE with low-pressure dilatation <12 atm (n = 143) or conventional BE stents (n = 136). Thereafter, acute results and long-term outcomes were compared. Baseline patient and angiographic characteristics were similar in two groups. The incidence of procedural complications, such as slow flow, side branch occlusion, and edge dissection were significantly lower in the SE group than in the BE group (overall: SE, 17; BE, 35; P < 0.01), and the occurrence of myocardial infarction tended to be lower in SE than in BE (SE, 1; BE, 4; not significant). Although acute gain was significantly smaller with SE than BE (SE, 2.21 +/- 0.65 mm; BE, 2.42 +/- 0.62; P < 0.01), probably due to gradual expansion of the SE stent, nearly identical minimum luminal diameters on follow-up angiography (SE, 2.14 +/- 0.92 mm vs. BE, 2.22 +/- 0.93; not significant) and similar angiographic restenosis (SE, 18.1% vs. BE, 20.5%). and TLR rates (SE, 16.1% vs. BE, 14.0%) were apparent. This prospective randomized trial demonstrates that SE stents with low-pressure dilatation is safe and effective strategy for treating coronary arterial stenosis.


Type B monoamine oxidase activity in human brain malignant tumors.
An increase of monoamine oxidase (MAO) activity was observed in Central Nervous System (CNS) malignant tumors, but the isoform responsible was not identify (Marcozzi et al., 1985). In the present work we report additional data in order to ascertain whether the type A or B MAO isoform is increased in some malignant human tumors of CNS. In the homogenated tissues the amine oxidase activity was determined by the chemiluminescent method, using different and specific substrates or inhibitors of MAO A and B and copper-dependent enzymes. 19 samples from 4 different types of tumors and relative peritumoral tissues were analysed. The highest activity of was imputable to type B MAO.


Serial changes in coagulant activities after thrombolytic therapy for acute myocardial infarction.
Early reocclusion and bleeding complications are still unresolved problems in thrombolytic therapy for acute myocardial infarction (AMI). In the present study, 16 patients treated with either fibrin-specific tissue-type plasminogen activator (t-PA) or nonspecific urokinase (UK) were studied to determine the effects of thrombolytic therapy on serial hemostatic states. Hemostatic states of each patient were estimated by measuring various plasma markers at one- to two-hour intervals during the first six hours of therapy, daily during the next three days, and subsequently on day 7. Two markers of plasma thrombin generation, thrombin antithrombin III complex (TAT) and prothrombin fragment 1 + 2 (F 1 + 2), showed an activated coagulant state immediately after thrombolytic therapy. The amount of thrombin generation indicated by these markers showed significant positive correlation with direct markers of fibrinolysis such as fibrin degradation products (FDP), while it did not show any correlation with the markers for plasmin generation. The potential for coagulation as indicated by prothrombin time (%) decreased with thrombolysis using fibrin nonselective agents, owing perhaps to destruction of coagulant factors by free plasmin. Fibrinolytic activity induced by thrombolytic therapy for AMI caused transient activation of the coagulant system, which could contribute to early reocclusion. Fibrin nonselective agents decreased the potential for coagulation by destroying clotting factor through the generation of free plasmin. These data provide theoretical support for simultaneous administration of anticoagulant therapy with fibrin-specific thrombolytic agents.


[Formation and reorganization of the early photoreception area in the eyes of sturgeon embryos and prelarvae. Radioautographic study].
A study of the development of eye retina in sturgeons (Acipenser güldenstädti and A. stellatus) by means of autoradiography has shown that during embryogenesis the cells of the high light sensitivity region complete the cycle of proliferation prior to the stage 29, what corresponds to the completion of proliferation of the retina cells in anurans and mammals, rather than at the stage 33, as was considered previously on the basis of the light microscopy morphological studies of differentiation. The cells of definitive retina begin to complete the cycle of proliferation at the stage 35 and the mass completion occurs at the stage 37. Some parameters of mitotic cycle were determined in the cells of definitive retina at the stages 34 and 37 and they proved to be similar with the corresponding parameters of the retina cells in anurans. The time of G2 period equals 2.5 hrs, that of S period 14 hrs and the whole mitotic cycle lasts 21.5 hrs. The transformation of the retina of high light sensitivity region in the definitive retina proceeds, mainly, by means of migration of the cells in this zone from the zone of intensive proliferation surrounding the high light sensitivity region. This transformation proceeds by means of morphological rearrangement of metamorphosis type.


[Medial collateral ligament of the knee and its surroundings: MRI findings of normal and abnormal structures].
Normal and abnormal structures of the medial corner of the knee were evaluated with coronal and axial MR images. MRI revealed 35 medial collateral ligament (MCL) tears and 61 medial meniscus (MM) tears in 200 consecutive examinations. Just under the MCL, little or no fluid retention was identified between the superficial and deep layers of the MCL or between the MM and MCL in normal knees and in cases of MM tears. At the anterior aspect of the MCL, the deep layer merges with the capsule of the suprapatellar bursa, potentially leaving space for fluid retention. Fluid collection posterior to the MCL was demonstrated in a few cases. Fluid retention with edematous swelling just under the MCL was noted in the cases of MCL tears. MM-MCL distances in the cases of normal structure, MM tears and MCL tears were 2.1 mm, 2.7 mm and 4.7 mm, respectively. The deep layer of the MCL, which was enhanced by the presence of joint fluid, was identified in 71% of cases.


Airway smooth muscle: immunomodulatory cells?
Evidence suggests that airway smooth muscle, the most important cell modulating bronchomotor tone, plays an important immunomodulatory role in the orchestration and perpetuation of airway inflammation. The signaling pathways that modulate leukocyte function may be disparate from those found in resident effector cells such as airway smooth muscle, fibroblasts, and epithelial cells. Further investigation and understanding of the pivotal signaling pathways that modulate airway smooth muscle cell release, secretion of chemokines/cytokines, and expression of cell adhesion molecules may offer new therapeutic approaches in the treatment of asthma.


User satisfaction with in-patient mental health services.
Although a wealth of literature regarding lay evaluation or satisfaction with health services exists, a paucity of literature is available about satisfaction with mental health services. Much of this literature is fraught with methodological problems. The study described, using both quantitative and qualitative methodology, investigated how users of in-patient mental health services evaluated these services with particular reference to the areas of the admission process, treatment, ward environment and safety. The findings confirmed the broad outcomes reported in the literature, in that they demonstrated the mismatch between quantitative and qualitative data. Global satisfaction ratings were generally positive; however, more specific questions yielded less positive outcomes. Semi-structured interviews reported some important areas of dissatisfaction, including a lack of information regarding treatment and services. Fears relating to safety were expressed equally by male and female users. Further work in this area is required with larger samples, and with specific reference to the experience of ethnic minorities and those detained under the Mental Health Act.


Common mechanisms govern the expression of p21ras and class II MHC antigens in the murine placenta.
It has been shown that there is an inverse as well as a direct correlation between class II MHC antigen expression and the p21ras protein, depending on the cell type. By using trophoblastic cells derived from the spongiotrophoblast and labyrinthine trophoblast, the two major components of the murine placenta, we have examined the p21ras expression in these populations and how this correlates with the induction of class II MHC antigens. It has been shown that although only a small number of cells express the p21ras and class II proteins, they can be induced to express higher levels of these markers by two different treatments. Thus, gamma-interferon (gamma-IFN) induces p21ras and class II protein expression in spongiotrophoblast-derived cells, whereas 5-Azacytidine (5-AzaC) induces expression of these antigens in labyrinthine trophoblast-derived populations. Furthermore, it has been demonstrated that there is a direct correlation between the two markers, as blocking antibody to p21ras cancels the ability of gamma-IFN and 5-AzaC to induce class II antigens. As previous work from this laboratory has shown that in vivo class II induction in the placenta leads to fetal abortion, the present results suggest that both proteins are involved in a common signal transduction pathway which may lead to disruption of fetal membranes and fetal loss.


Eliciting patient disutilities for the adverse outcomes of cardiopulmonary resuscitation.
in helping patients decide about treatments, such as whether to authorize cardiopulmonary resuscitation (CPR), physicians typically present information about the possible outcomes and their likelihoods. The aim of this study was to elicit patient disutilities for the adverse outcomes of cardiopulmonary resuscitation (CPR) using the methodology of NH Anderson's functional theory of cognition and to determine how patients integrate the disutility and the likelihood of an outcome. 77 French adults rated scenarios of possible outcomes of CPR on a linear scale with anchors "what would be the best (or worst) for me." In 25 of the 27 scenarios, the result would be either total recovery or one of five adverse outcomes (chest injury, mild reversible brain damage, severe irreversible brain damage, death after intensive care, immediate death) with one of five likelihoods (one to five chances out of ten). In the other two, the only possible result was either total recovery or immediate death. the mean disutilities relative to 0 for chest injury and 100 for severe brain damage were 13 for mild brain injury, 68 for death after intensive care, and 69 for immediate death. The graphs of the ratings of each adverse outcome in relation to its frequency were fan-shaped, showing that participants integrated this information multiplicatively. the functional theory of cognition provides an alternate method of eliciting patient utilities for the outcomes of CPR and supports clinicians' assumption that people combine utility and likelihood multiplicatively.


Production of a monoclonal antibody (2B44) reactive on a shared epitope on dendritic reticulum cells, smooth muscle cells of vessels and Reed-Sternberg cells.
Lymph node cells from a patient with Hodgkin's disease (HD) were cultured without Epstein-Barr virus (EBV) or leukine adjuvant. A cell line (719-AB) emerged from the culture after four weeks. The cell line express CD20 (79%), CD 21 (30%), CD30 (63%), CD 35 (61%) antigens and weakly CD25 (19%). using Southern Blot technique, the existence of specific EBV DNA and polyclonal immunoglobulin genes rearrangement were observed in the cell line. In order to obtain a monoclonal antibodies (MoAb), mice Balb/C were immunized with this cell line. The splenic cells suspension of immunized animals were fused with the mouse myeloma NS1. Antibody IgM kappa from secreting clones 2B44 was studied using both indirect immunofluorescence with labeled anti-mouse immunoglobulin and immunohistochemistry based on alkaline phosphatase/antiphosphatase complex (APAAP) and ModAMeX technique on a panel of normal or pathological cells. Normal peripheral lymphocytes, monocytes, polymorphonuclear cells, and erythrocytes, did not react. The MoAb 2B44 recognized the dendritic reticulum cells and the smooth muscle cells of vessels on frozen section and paraffin section from HD or reactive lymph nodes. On specially processed paraffin sections (ModAMeX) Reed-Sternberg cells (RSC) were reactive with 2B44 MoAb (in 2 cases out of 5 tested). The molecular weight of the antigen recognized by 2B44 MoAb is of 37 kd. The description of a new epitope shared by different histological components might be of interest for defining a new cluster and better understanding the nature of RSC.


Protein kinase C-theta (PKCtheta), a potential drug target for therapeutic intervention with human T cell leukemias.
The link between apoptosis and malignant cell growth is firmly established, and various forms of therapy in cancer, e.g., the use of DNA-damaging chemotherapeutic drugs, are based on the principle of inducing apoptosis in malignant cells. However, in many known instances, tumor cells develop resistance to apoptosis through various mechanisms. Thus, interventions designed to facilitate tumor cells apoptosis are likely to have a therapeutic benefit. PKCtheta, which is expressed relatively selectively in T cells, plays an important role in mature T cell activation and proliferation upon its translocation to the plasma membrane. PKCtheta is necessary for induction of the interleukin-2 (IL-2) gene because the transcription factors AP-1 and NF-kappaB, which are essential for IL-2 gene promoter activation, are main targets of PKCtheta. Recent studies revealed that PKCtheta provides an important survival signal that protects leukemic T cells from Fas- or UV-induced apoptosis. These findings and the constitutive localization of PKCq in the membrane of some leukemic T cells suggests that it plays a role in leukemic T cell survival and/or proliferation, and that selective PKCtheta-inhibitory strategies may facilitate elimination of malignant T cells. The high-affinity IL-2 receptor (IL-2Ralpha) is a major target of receptor-directed therapy in several human diseases, and it is constitutively expressed by the malignant cells in some T cell leukemias, suggesting an autocrine IL-2/IL-2R loop that participates in the expansion of leukemic IL-2R(+) cells. Therefore, given the essential role of PKCtheta in IL-2 production, IL-2 gene regulation by PKCtheta could also be of therapeutic interest.


Management of hemobilia and persistent biliary fistula after blunt liver trauma.
A 10-year-old girl had hemobilia and a biliocutaneous fistula after blunt abdominal trauma. Embolization of the right hepatic artery occluded the hepatic artery aneurysm, but the cutaneous biliary fistula persisted despite prolonged (8 months) conservative management including sphincter decompression with an endoscopically placed biliary stent. Roux-en-Y fistuloenterostomy eventually cured the bile leak.


Preoperative assessment of advanced gastric carcinoma using computed tomography.
The role of computed tomography (CT) for the staging of gastric carcinoma is controversial. The purpose of this study was to evaluate the utility of CT in assessing the perigastric spread of advanced gastric carcinoma. The study included 56 patients who underwent dynamic CT and laparotomy for the treatment of node-positive gastric adenocarcinoma. Preoperative CT findings were compared with surgical findings, and diagnostic accuracy was estimated. Sensitivity, specificity, and accuracy of preoperative CT in determining the perigastric tumor spreads were 33, 97, and 73% in pancreatic invasion, 36, 97, and 70% in level III lymph node involvement, and 89, 98, and 96% in liver metastasis. Peritoneal dissemination was not detected in 15 of 56 patients (27%), and stage IV disease was not diagnosed correctly in 18 of 40 patients (45%). Radiologists and surgeons must remember that pancreatic invasion, extended lymph node metastasis, and peritoneal dissemination are sometimes overlooked in CT examination in patients with advanced gastric carcinoma.


Atorvastatin induces mitochondrial dysfunction and cell apoptosis in HepG2 cells via inhibition of the Nrf2 pathway.
Atorvastatin (ATO) is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used to treat hypercholesterolemia. However, clinical application is limited by potential hepatotoxicity. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular antioxidants, and oxidative stress is implicated in statin-induced liver injury. This study investigated mechanisms of ATO-induced hepatotoxicity and potential mitigation by Nrf2 signaling. ATO reduced Nrf2 and antioxidant enzyme superoxide dismutase-2 (SOD2) expression in human hepatocarcinoma HepG2 cells. ATO also induced concentration-dependent HepG2 cell toxicity, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential (MMP) and cellular adenosine triphosphate (ATP). Further, ATO induced mitochondria-dependent apoptosis as indicated by increased Bax/Bcl-2 ratio, cleaved caspase-3, mitochondrial cytochrome c release and Annexin V-fluorescein isothiocyanate/propidium iodide staining. Tert-butylhydroquinone enhanced Nrf2 and SOD2 expression, and partially reversed ATO-induced cytotoxicity, ROS accumulation, MMP reduction, ATP depletion and mitochondria-dependent apoptosis. In conclusion, the present study demonstrates that ATO induces mitochondrial dysfunction and cell apoptosis in HepG2 cells, at least in part, via inhibition of the Nrf2 pathway. Nrf2 pathway activation is a potential prevention for ATO-induced liver injury.


Differential regulation of tyrosine phosphorylation in tumor cells by contortrostatin, a homodimeric disintegrin, and monomeric disintegrins echistatin and flavoridin.
The homodimeric disintegrin contortrostatin was compared directly to the monomeric disintegrins echistatin and flavoridin for the ability to affect protein tyrosine phosphorylation in tumor cells. It was observed that contortrostatin had a dramatic effect on the tyrosine phosphorylation status of several proteins in T24 human bladder cancer cells, including robust induction of phosphorylation of proteins in the range of 120-140 kDa. Echistatin alone had no effect on tyrosine phosphorylation in T24 cells, but dose-dependently inhibits the effects of contortrostatin when both are added simultaneously. Among the proteins that undergo tyrosine phosphorylation in response to contortrostatin treatment is CAS, a 130 kDa adapter protein involved in integrin signaling. Flavoridin alone was found to have no effect on CAS, but can completely block contortrostatin-induced phosphorylation of this protein in MDA-MB-435 cells. These observations strongly suggest that the homodimeric structure of contortrostatin functionally distinguishes it from other monomeric members of the disintegrin family.


Accuracy of enzyme-linked immunosorbent assays for quantification of antibodies against Aleutian mink disease virus.
There is a growing interest among mink ranchers to select their stock for tolerance to the Aleutian mink disease virus (AMDV). Enzyme-linked immunosorbent assays (ELISA) are used to identify mink which have low anti-AMDV antibody titres and are expected to tolerate the AMDV infection. The objective of this study was to calculate the accuracy of three ELISA systems which were performed on blood or serum of AMDV-inoculated American mink (Neovison vison) at five laboratories in Canada, USA, Finland, the Netherlands and Denmark. The accuracy was determined by comparing the ELISA results with antibody titres measured by the counter-immunoelectrophoresis (CIEP) using 10 two-fold serial dilutions of the plasma. Antibody titres of 880 black mink which were inoculated with a spleen homogenate from a naturally infected mink were measured between 16 and 176 weeks post-inoculation. Each ELISA result from every laboratory covered a wide range of antibody titres and the Spearman's rank correlation coefficients between CIEP and ELISA results from different laboratories varied between 0.41 and 0.83, indicating a low to moderate accuracy of ELISA systems for ranking mink by antibody titre. The recombinant VP2-based ELISA used in the Netherlands and Finland ranked the mink by antibody titres more accurately than did the AMDV-G-based ELISA platforms developed in Denmark and the USA, suggesting that the source of antigen was one of the factors affecting the accuracy of ELISA results. It was concluded that the ELISA systems, particularly those based on AMDV-G antigen, require further refinement to improve their accuracy for ranking mink by antibody titre.


6-Thioguanine treatment of psoriasis: experience in 81 patients.
Despite recent innovations a considerable number of patients with psoriasis cannot be successfully treated by current therapies. Our purpose was to summarize our 18-year experience with the antimetabolite 6-thioguanine in the management of patients with psoriasis. We retrospectively studied 81 patients who were treated with 6-thioguanine. A variety of schedules were used to find the optimal schedule. Forty-eight percent of the patients either had been treated with methotrexate or were excluded from receiving methotrexate because of liver or kidney disease. Forty-nine percent of patients with plaques were effectively maintained with 6-thioguanine for a median of 33 months. Four of five patients with palmoplantar pustular psoriasis experienced substantial benefit. The most common side effect was myelosuppression. 6-Thioguanine is an effective therapy for psoriasis and should be considered for patients who have failed to respond to other systemic agents.


Omalizumab: where does it fit into current asthma management?
Omalizumab (Xolair), a monoclonal antibody, is a new agent that blocks the allergic cascade at its primary step. This drug offers substantial promise for patients with moderate-to-severe, persistent allergic asthma that is not well controlled. But due to the cost of the drug, limitations on dosage, and available clinical trial data, it is not a first-line therapy. This review discusses how this drug works, which patients will be candidates for it, and the practical aspects of using it.


Nonlinear diffusion of a growth inhibitory factor in multicell spheroids.
A mathematical model is presented for the production of a growth inhibitory factor (GIF) within a multicell spheroid. The model is based on the assumption that the GIF diffuses within the spheroid in a nonlinear spatially dependent manner. This is in contrast with previous models, in which the nonlinearity was assumed in the production term. The results of the new model are compared with those of previous models and with experimental data.


Naloxone potentiates epinephrine's pressor actions in endotoxemic rats.
Naloxone's pressor effects in shock may be mediated through antagonism of endogenous opioid inhibition of sympathoadrenal catecholaminergic systems. Since circulating catecholamine levels are not further elevated by naloxone in endotoxemic animals, it is possible that naloxone acts upon opiate receptors to enhance catecholamine actions at the receptor or postreceptor level. To investigate this hypothesis, we sought to determine whether naloxone treatment would augment the pressor actions of exogenous catecholamines (epinephrine) in normal and endotoxemic rats. Naloxone (3 mg/kg intravenous [i.v.] bolus followed by 3 mg/ml/hr infusion) significantly augmented the pressor response to 10, 20, and 50 micrograms/kg of i.v. epinephrine by 69%, 48% and 14%, respectively, in endotoxin (5 mg/kg, LD20, i.v.) -treated rats but not in normal rats. Likewise, the duration of the pressor response to epinephrine was significantly increased by naloxone. These findings suggest that the coadministration of naloxone and epinephrine may be of benefit in the treatment of shock.


Role of polyamines and NMDA receptors in ethanol dependence and withdrawal.
This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chair was John M. Littleton. The presentations were (1) Examination of ethanol spermine and acamprosate actions on native and recombinant NMDA receptors, by David Lovinger; (2) Ethanol inhibition of NMDA neurotoxicity on the polyamine site in cerebellar granule cells, by Sture Liljequist; (3) Alterations in expression of NMDA receptor subunits during ethanol exposure and withdrawal, by Raj Ticku; (4) Alterations in polyamine synthesis and release as a potential mechanism for ethanol dependence and withdrawal, by Izuru Matsumoto; (5) The role of polyamines in neurotoxicity induced by alcohol withdrawal in vitro, by John Littleton; and (6) Agmatine reduces some of the effects of "third trimester" alcohol exposure using a rodent model, by Susan Barron.


Non-immunized natural human heavy chain CDR3 repertoires allow the isolation of high affinity peptides mimicking a human influenza hemagglutinin epitope.
In this study we constructed two phage libraries displaying non-immunized natural human IgM derived HCDR3 repertoires. One library was structurally constrained by a Gly to Cys substitution at position 104 enabling the formation of a disulfide bridge with the Cys at position 92. Panning of these libraries on an anti-human influenza hemagglutinin (HA) antibody resulted in the selection of 16 different HCDR3 loops displaying different degrees of sequence homology with the HA epitope. The specificity of the HCDR3 loops recovered from the structurally constrained library was confirmed by competition assays using the HA epitope. Only one of these HCDR3 peptides contained Cys104. Structural analysis of these sequences revealed that the loss of Cys104 was associated with an increased preference for the formation of the type I beta-turn required for high affinity binding to the antibody. Affinity studies confirmed that the HCDR3 peptides containing the sequence YDVPDY and Gly104 had affinities in the nanomolar range (K(d)=7.6 nM) comparable to the HA epitope. These findings provided evidence that the recovered HCDR3 sequences may bind to their target in a conformation that is unreachable by the parental antibody from which the HCDR3 was derived. Furthermore, the isolation of target-specific and high affinity binders demonstrates the value of HCDR3 libraries as a source of 'biologically randomized' sequences of human origin for the identification of peptidic lead molecules.


Inhibition of human immunodeficiency virus type 1 reverse transcriptase and ribonuclease H activities by constituents of Juglans mandshurica.
From the stem-bark of Juglans mandshurica, two new naphthalenyl glucopyranosides, 1,4,8-trihydroxynaphthalene 1-O-[alpha-L-arabinofuranosyl-(1-->6)-beta-D-glucopyranoside] (1) and 1,4,8-trihydroxynaphthalene 1-O-beta-D-[6'-O-(3",5"-dihydroxy-4"-methoxybenzoyl)]glucopyranosi de (4), and two new alpha-tetralonyl glucopyranosides, 4 alpha,5,8-trihydroxy-alpha-tetralone 5-O-beta-D-[6'-O-(3",5"-dihydroxy-4"-methoxybenzoyl)]glucopyranosi de (7) and 4 alpha,5,8-trihydroxy-alpha-tetralone 5-O-beta-D-[6'-O-(3",4",5"-trihydroxybenzoyl)]glucopyranoside (8), were isolated together with three known naphthalenyl glucopyranosides (2, 3 and 5), one alpha-tetralonyl glucopyranoside (6), four flavonoids (9-12), and two galloyl glucopyranosides (13, 14). Amongst the isolated compounds, 1,2,6-trigalloylglucopyranose (13) and 1,2,3,6-tertagalloylglucopyranose (14) exhibited the most potent inhibition of reverse transcriptase (RT) activity with IC50 values of 0.067 and 0.040 microM, respectively, while the latter compound also inhibited ribonuclease H (RNase H) activity with an IC50 of 39 microM, comparable in potency to illimaquinone used as a positive control. 1,4,8-Trihydroxy-naphthalene 1-O-beta-D-glucopyranoside (2), 1,4,8-trihydroxynaphthalene 1-O-beta-D-[6'-O-(4"-hydroxy-3",5"-dimethoxybenzoyl)]glucopyranoside (3) and 8 showed moderate inhibition against both enzyme activities, and inhibitory potency of 2 against RNase H activity (IC50 = 156 microM) was slightly greater than that against the RT activity (IC50 = 290 microM). The inhibitory potencies of 4 alpha,5,8-trihydroxy-alpha-tetralone 5-O-beta-D-[6'-O-(4"-hydroxy-3",5"-dimethoxybenzoyl)] glucopyranoside (6), 7 and 8 against RT activity increased accompanied by an increase in the number of free hydroxyls on the galloyl residues, as represented by the IC50 values of > 500, 330 and 5.8 microM, respectively.


GLUT1 is associated with sphingolipid-organized, cholesterol-independent domains in L929 mouse fibroblast cells.
Glucose is a preferred metabolite in most mammalian cells, and proper regulation of uptake is critical for organism homeostasis. The glucose transporter 1 (GLUT1) is responsible for glucose uptake in a wide variety of cells and appears to be regulated in a tissue specific manner. Therefore, a better understanding of GLUT1 regulation within its various cellular environments is essential for developing therapeutic strategies to treat disorders associated with glucose homeostasis. Previous findings suggest that plasma membrane subdomains called lipid rafts may play a role in regulation of GLUT1 uptake activity. While studying this phenomenon in L929 mouse fibroblast cells, we observed that GLUT1 associates with a low density lipid microdomain distinct from traditionally-defined lipid rafts. These structures are not altered by cholesterol removal with methyl-β-cyclodextrin and lack resistance to cold Triton X-100 extraction. Our data indicate that the GLUT1-containing membrane microdomains in L929 cells, as well as GLUT1's basal activity, are instead sphingolipid-dependent, being sensitive to both myriocin and sphingomyelinase treatment. These microdomains appear to be organized primarily by their lipid composition, as disruption of the actin cytoskeleton or microtubules does not alter the association of GLUT1 with them. Furthermore, the association of GLUT1 with these microdomains appears not to require palmitoylation or glycosylation, as pharmacologic inhibition of these processes had no impact on GLUT1 density in membrane fractions. Importantly, we find no evidence that GLUT1 is actively translocated into or out of low density membrane fractions in response to acute activation in L929 cell.


Comparison between short-term renal haemodynamic effects of propranolol and nadolol in essential hypertension: a cross-over study.
The effect of 4-6 weeks' treatment with propranolol and nadolol on effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) was studied, in 14 patients with essential hypertension, in single blind, random and cross-over design. Both drugs caused comparable effective lowering of pulse and blood pressure. When taken as the first drug, propranolol caused significant reduction in ERPF and GFR and a rise in filtration fraction (FF) and renal vascular resistance (RVR), whereas nadolol caused distinct rise in ERPF and a fall in FF and RVR but GFR remained unchanged. These haemodynamic effects were reduced when propranolol was given immediately after the withdrawal of nadolol and were obviated when nadolol followed propranolol therapy. This suggested a carry-over effect of the first drug into the second phase of treatment. We conclude that with short term therapy in essential hypertension, propranolol has a renal vasoconstrictor and nadolol a vasodilator effect.


ProgeniDB: a novel cell lineage database for generation associated phenotypic behavior in cell-based assays.
ProgeniDB is a web-accessible cell lineage database, which comprises data derived from time-lapse microscopy image sequences, using our novel encoding software tool called ProgeniTRAK. This database provides information on qualitative and quantitative changes in cellular dynamics in response to anti-cancer drugs variation, which is critical for pharmacodynamic modeling and validation. The lineage data for each progenitor cell centers around the construction of a bifurcation map, locating in both space and time critical cellular events such as cell division and cell death. This database provides the opportunity to select a set of lineages based on different experimental constraints and observe the associated phenotypic behavior of progenitor cells. The output generated from this database depicts the cellular dynamic of selected population which can be downloaded to explore and exploit in relation to hypothesis-driven drug discovery. A case study is presented where we interrogate drug-induced perturbations on ensuing cell lineages. The database is available at http://biodiversity.cs.cf.ac.uk/cymart/progenidb.html.


Cytolytic T cell hybridomas. II. Interleukin 2-independent cytolytic variants.
Interleukin 2 (IL2)-dependent cytolytic hybrids usually loose IL2 dependence and cytolytic activity concomittantly. Here we describe an exceptional IL2-independent variant which lost IL2 receptor but retained cytolytic activity. When the IL2-independent cytolytic hybrid cells were fused with IL2-dependent cytolytic clones which express IL2 receptors constitutively, IL2-dependent hybrids were obtained. This suggests that the expression of IL2 receptors can interfere with IL2-independent growth mechanisms.


Biodegradable cisplatin microspheres for direct brain injection: preparation and characterization.
The objectives of the present study were to prepare cisplatin loaded-PLGA microspheres that are suitable for direct brain injection and to characterize them in terms of their physicochemical properties, in vitro drug release, and self-removal mechanism. The microspheres were prepared by emulsification/solvent evaporation method using PLGA (50:50) as the biodegradable matrix forming polymer. The physicochemical characterization encompassed the following: surface morphology, particle size, entrapment efficiency, surface area, and density. The in vitro release and in vitro degradation studies were performed in phosphate buffer and in 10% rat brain preparation. SEM micrographs revealed that the microspheres have a rough porous surface and a smooth interior. Particle size typically ranged from 180 to 250 microns with an average of 230 T microns. Entrapment efficiency was approximately 70% and was found to be dependent on the particle size. Surface area and density ranged from 0.038 to 0.025 m2/g and from 1.44 to 1.39 g/cm3, respectively. Both were also dependent on particle size. In the in vitro release study in phosphate buffer, approximately 80% of cisplatin was released over 30 days, after which the release rate plateaued. The release profile in 10% rat brain preparation was comparable in shape to that obtained in phosphate buffer. However, the release rate was lower and the total amount released by the end of the study was only 55% of the total cisplatin content. The degradation of PLGA microspheres in phosphate buffer and in rat brain homogenate correlated well with the respective release profiles. Based on the evidence of self-removal and the sustained release of cisplatin for over a month, cisplatin-loaded PLGA microspheres may be useful for local delivery to brain tumors.


Hypertension, hyperlipidemia, and abdominal obesity and the development of microalbuminuria in patients with non-insulin-dependent diabetes mellitus.
The hyperlipidemia syndrome (also called syndrome X or the deadly quartet) is a recognized constellation known to increase cardiovascular mortality, but its effect on renal decline is not well-described. This study examined the differential effects of hypertension, hyperlipidemia, and abdominal obesity on overnight urinary albumin excretion ratios (UAERs) among patients with non-insulin-dependent diabetes mellitus (NIDDM), who by definition possess the remaining component of the syndrome, insulin resistance. We conducted a survey of 317 primary care NIDDM patients measuring waist-to-hip ratios, fasting lipid levels and glycemic values, and overnight UAERs. The study was carried out between January 1989 and June 1991. Using logistic regression controlling for age, race, sex, duration of NIDDM, and smoking status, elevated glycosylated hemoglobin (odds ratio [OR] = 1.95, 95 percent confidence interval [CI] = 1.16-3.27) or the addition of one component of the deadly quartet to pure diabetes doubled or tripled the odds of an elevated UAER (NIDDM plus obesity OR = 2.00, 95 percent CI = 1.02-3.93; NIDDM plus hypertension OR = 3.45, 95 percent CI = 1.38-8.63; NIDDM plus hyperlipidemia OR = 1.60, 95 percent CI = 0.53-4.81). In a dose-response manner, two additional factors exerted additive effects; all three additional factors combined with pure NIDDM multiplied the effect, with an odds ratio of 9.34 (95 percent CI = 2.24-38.9). These data quantify the incremental effects of abdominal obesity, hypertension, and hyperlipidemia on abnormal UAERs among NIDDM patients and strongly suggest the need for aggressive and simultaneous correction of multiple risk factors to prevent end organ damage in this population.


Riskier-than-expected occlusive treatment of ruptured posterior communicating artery aneurysms: treatment and outcome of 620 consecutive patients.
OBJECTIVE: Occlusive treatment of posterior communicating artery (PCoA) aneurysms has been seen as a fairly uncomplicated procedure. The objective here was to determine the radiological and clinical outcome of patients after PCoA aneurysm rupture and treatment and to evaluate the risk factors for impaired outcome. METHODS: In a retrospective clinical follow-up study, data were collected from 620 consecutive patients who had been treated for ruptured PCoA aneurysms at a single center between 1980 and 2014. The follow-up was a minimum of 1 year after treatment or until death. RESULTS: Of the 620 patients, 83% were treated with microsurgical clipping, 8% with endovascular coiling, 2% with the two procedures combined, 1% with indirect surgical methods, and 6% with conservative methods. The most common procedural complications were treatment-related brain infarctions (15%). The occurrence of artery occlusions (10% microsurgical, 8% endovascular) was higher than expected. Most patients made a good recovery at 1 year after aneurysmal subarachnoid hemorrhage (modified Rankin Scale [mRS] score 0-2: 386 patients [62%]). A fairly small proportion of patients were left severely disabled (mRS score 4-5: 27 patients [4%]). Among all patients, 20% died during the 1st year. Independent risk factors for an unfavorable outcome, according to the multivariable analysis, were poor preoperative clinical condition, intracerebral or subdural hematoma due to aneurysm rupture, age over 65 years, artery occlusion on postoperative angiography, occlusive treatment-related ischemia, delayed cerebral vasospasm, and hydrocephalus requiring a shunt. CONCLUSIONS: Even though most patients made a good recovery after PCoA aneurysm rupture and treatment during the 1st year, the occlusive treatment-related complications were higher than expected and caused morbidity even among initially good-grade patients. Occlusive treatment of ruptured PCoA aneurysms seems to be a high-risk procedure, even in a high-volume neurovascular center.


Treatment of class III multiple gingival recessions: Prognostic factors for achieving a complete root coverage.
This report is intended to present a supplemental analysis of data from a prior report (Aroca et al., ) to investigate factors associated with a complete root coverage at 1 year. The purpose of the prior report was to investigate at 1 year the adjunction effect of EMD for the treatment of Miller's class III recession defects using a coronally advanced modified tunnel/CTG technique with (test group) or without (control group). The purpose of this report was to investigate additional factors associated with root coverage in the same data set. On the 138 observations collected from 20 patients, a regression model was used to highlight the relationship between the percentages of root coverage (RC) and three following covariates: the distance from the tip of the papilla and the contact point (DCP) at baseline, the group membership (control vs. test) and tooth position in the mouth (maxillary vs. mandibular). The statistical analysis showed that there was a significant effect of the DCP at baseline (p = 0.01) and of the tooth type (p < .001) on the percentage of RC at 1 year, whereas no significant difference between the two techniques (group membership effect) was shown (p = 0.69). The probability to obtain a complete root coverage decreases when the DCP at baseline increases. Moreover, maxillary teeth are more likely to give better RC than mandibular teeth. However, in this analysis similar to the last, there was no group effect.


Protective efficacy of high-passage avian pneumovirus (APV/MN/turkey/1-a/97) in turkeys.
A U.S. isolate of avian pneumovirus (APV), APV/MN/turkey/1-a/97, was attenuated by serial cell culture passages in chicken embryo fibroblasts (seven passages) and Vero cells (34 passages). This virus was designated as APV passage 41 (P41) and was evaluated for use as a live vaccine in commercial turkey flocks. The vaccine was inoculated by nasal and ocular routes in 2-to-4-wk-old turkeys in 10 turkey flocks, each with 20,000-50,000 birds. Only 2 birds per 1000 birds were inoculated in each flock with the expectation that bird-to-bird passage would help spread the infection from P41-exposed birds to their respective flock mates. The virus did spread from vaccinated birds to the entire flock within 10 days as detected by reverse transcription-polymerase chain reaction. Mild respiratory illness was observed in a few birds 12 days postvaccination in 2 of 10 flocks. Within 3 wk postvaccination, all flocks became seropositive for APV antibodies as measured by enzyme-linked immunosorbent assay. In an additional flock, the virus was administered to all turkeys simultaneously in drinking water and seroconversion occurred within 2 wk. All 11 flocks remained seropositive until 10 wk postvaccination. When compared with unvaccinated flocks on the same farm from the previous year, the medication cost, total condemnation, and mortality rates attributed to APV were lower in P41-vaccinated flocks. When birds from vaccinated flocks were challenged with virulent APV under experimental conditions, no clinical signs were observed at 2, 6, and 10 wk postvaccination, whereas in the control unvaccinated birds, respiratory illness and virus shedding occurred after challenge. These results indicate that P41 administered by the nasal and ocular routes, and by drinking water, causes seroconversion and induces protection from virulent APV challenge for at least 10 wk.


Activity spaces in place and health research: Novel exposure measures, data collection tools, and designs.
Activity space research provides a framework to consider mobility while linking environments to behaviors in the study of neighborhood effects on health. Increased use of wearable location sensors provides new opportunities to observe and analyze fine-grained spatial and temporal information on individuals' mobility patterns, environmental exposures and behaviors; however, these analysis does not easily translate into causal inference. Additional dimensions underlying behavioral decision-making likely influence or even modify environmental effects on behaviors. This commentary discusses how further progresses in exposure measurement, integration of data collection tools, and development of study designs could support future interventions to optimize how environments shape health profiles and inequities.


[Rational approach to peripheral arterial occlusive diseases].
A growing proportion of over 65-year-old persons in the population will increasingly confront physicians with peripheral arterial occlusive disease. Intermittent claudication is the characteristic symptom of stage II disease at which most patients consult their physician. Known risk factors like cigarette smoking, diabetes, hypertension and hyperlipidemia have to be assessed. Manifestations of atherosclerosis in other vascular beds such as carotids and coronaries should be sought. Clinical angiologic evaluation with inspection, palpation of pulses, auscultation of vessels at rest and after exercise as well as measurement of the walking distance permits assessment of peripheral perfusion quite well. Oscillography and Doppler-sonography are increasingly used. Duplex-scanning can replace angiography in many cases. Conventional and digital subtraction-angiography have their specific uses. Diagnostic and therapeutic measures recommended for peripheral arterial occlusive disease are summarized.


A highly sensitive canine telemetry model for detection of QT interval prolongation: studies with moxifloxacin, haloperidol and MK-499.
Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the beagle dog telemetry (Integrated Telemetry Services (ITS)) model as a preclinical predictor of QT interval prolongation in humans. Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with moxifloxacin (MOX), haloperidol (HAL), and MK-499, with a toxicokinetic (TK) evaluation in a separate group of dogs. In both cardiovascular and TK studies, MOX (0, 10, 30 and 100 mg/kg), HAL (0, 0.3, 1, 3 mg/kg) and MK-499 (0, 0.03, 0.3 and 3 mg/kg) were administered orally by gavage in 0.5% methylcellulose. Each dog received all 4 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle (0.5% methylcellulose) alone for 4 days. Significant increases in QT(c) were evident with 10, 30 and 100 mg/kg of MOX (C(max)< or =40 microM), 0.3, 1 and 3 mg/kg of HAL (C(max)< or =0.36 microM) and 0.3 and 3 mg/kg of MK-499 (C(max)< or =825 nM) with peak increases of 45 (20%), 31 (13%), and 45 (19%) ms, respectively (p< or =0.05). In conclusion, we have demonstrated that the ITS-telemetry beagle dog exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QT(c) interval ( approximately 3-6%) with MOX, HAL and MK-499 in the same range of therapeutic plasma concentrations attained in humans. Therefore, this dog telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.


[Esophageal intubation: Can it be avoided with the airway scope (Pentax-AWS)?].
Airway scope (AWS) is a rigid indirect laryngoscope with integrated tube guidance and can improve laryngeal exposure compared to the conventional direct laryngoscope. It is expected that the clear and improved laryngeal view obtained with AWS can eliminate the risk of esophageal intubation. We, however, experienced 3 cases of esophageal intubation out of 600 clinical cases with AWS in 15 month after its market release. Two cases were by novice anesthesiologists with fewer than 10 intubation experiences with AWS. Although they had had more than 100 intubation experiences with Macintosh laryngoscope, they did not have sharp eye for incorrect intubation with AWS. The third case was performed by an experienced laryngoscopist but it was difficult to identify the glottic opening because patient had distracted airway anatomy due to laryngeal tumor. In all cases esophageal intubation was immediately noticed and airway was secured uneventfully. We conclude that intubation under vision with improved laryngeal view is still not sufficient to prevent esophageal intubation.


Cell cycle-dependent localization of monoclonal antibodies raised against isolated Dictyostelium centrosomes.
The ultrastructure of the Dictyostelium centrosome is markedly different from that of the well known yeast spindle pole body and vertebrate centriole-containing centrosome. It consists of a box-shaped, layered core structure surrounded by a corona with dense nodules embedded in an amorphous matrix. For further structural and biochemical analyses of this type of centrosome we used highly enriched isolated Dictyostelium centrosomes as an antigen to raise 14 new centrosomal monoclonal antibodies. Immunofluorescence microscopy and Western blot analysis revealed that at least 10 of them were directed against different antigens. Immunofluorescence microscopy also showed that the monoclonal antibodies fell into three different groups: A) antibodies localizing to the centrosome during the entire cell cycle; B) antibodies staining the centrosome mainly during mitosis; and C) antibodies labeling centrosome associated structures. All antibodies, except one, exhibited a cell cycle-dependent staining pattern underscoring the highly dynamic properties of the Dictyostelium centrosome.


T-cell lines derived from lesional skin of lichen planus patients contain a distinctive population of T-cell receptor gamma delta-bearing cells.
Lichen planus is characterized by a dense infiltrate of T lymphocytes at the dermoepidermal junction. To determine the phenotypic and functional characteristics of the infiltrating lymphocytes, T-cell lines from normal and lesional skin from the same patients with lichen planus were established by culture with interleukin 2 followed by stimulation every 14 d with phytohemagglutinin and irradiated allogeneic feeder cells. Resultant T-cell lines were immunophenotyped by staining with monoclonal antibodies and their reactivity tested by determining their cytolytic activity to selected targets. T-cell lines from 13 lesional and nine normal biopsy specimens were studied. T-cell lines from normal skin were 61% CD4+ and 32% CD8+, whereas lines from lesional skin had significantly fewer CD4+ cells (13%) and more CD8+ cells (62%). T-cell lines from lesional skin contained a distinctive population of gamma delta T cells that was rarely present in lines derived from normal skin. We were able to culture gamma delta T cells out of the lesional skin of 12 of 13 patients. In these 12 patients, lesional T-cell lines were 17% gamma delta+ (range 2% to 47%). Only one T-cell line from normal skin contained significant numbers of gamma delta T cells. The gamma delta population from lesional skin was commonly V delta 1J delta 1+. These results suggest that CD8+ and TCR gamma delta+ T lymphocytes may be involved in the development or the maintenance of lichen planus.


Nitrogen fate in a subtropical mangrove swamp: Potential association with seawater-groundwater exchange.
Coastal mangrove swamps play an important role in nutrient cycling at the land-ocean boundary. However, little is known about the role of periodic seawater-groundwater exchange in the nitrogen cycling processes. Seawater-groundwater exchange rates and inorganic nitrogen concentrations were investigated along a shore-perpendicular intertidal transect in Daya Bay, China. The intertidal transect comprises three hydrologic subzones (tidal creek, mangrove and bare mudflat zones), each with different physicochemical characteristics. Salinity and hydraulic head measurements taken along the transect were used to estimate the exchange rates between seawater and groundwater over a spring-neap tidal cycle. Results showed that the maximum seawater-groundwater exchange occurred within the tidal creek zone, which facilitated high-oxygen seawater infiltration and subsequent nitrification. In contrast, the lowest exchange rate found in the mangrove zone caused over-loading of organic matter and longer groundwater residence times. This created an anoxic environment conducive to nitrogen loss through the anammox and denitrification processes. Potential oxidation rates of ammonia and nitrite were measured by the rapid and high-throughput method and rates of denitrification and anammox were measured by the modified membrane inlet mass spectrometry (MIMS) with isotope pairing, respectively. In the whole transect, denitrification accounted for 90% of the total nitrogen loss, and anammox accounted for the remaining 10%. The average nitrogen removal rate was about 2.07g per day per cubic meter of mangrove sediments.


Efficacy and safety of combination therapy with candesartan cilexetil and pioglitazone hydrochloride in patients with hypertension and type 2 diabetes mellitus.
To evaluate the efficacy and safety of combination therapy with candesartan cilexetil (CC) and pioglitazone hydrochloride (PIO) in patients with hypertension and type 2 diabetes mellitus. A 12-week, double-blind, randomized, parallel-group study in patients with mild-to-moderate essential hypertension and type 2 diabetes mellitus was followed by a 40-week, single-blind study. Patients (N = 377) were randomized to treatment with CC 8 mg/PIO 30 mg (n = 62), CC 8 mg/PIO 15 mg (n = 63), CC 4 mg/PIO 30 mg (n = 63), CC 4 mg/PIO 15 mg (n = 63), CC 8 mg/PIO 0 mg (n = 63), or CC 0 mg/PIO 30 mg (n = 63). Primary efficacy measures were changes in diastolic blood pressure (DBP) and HbA(1C) at Week 12. CC/PIO combination therapy improved blood pressure (BP)/glycemic control for 52 weeks. At the end of 12-week treatment period, DBP decreased to a significantly greater extent in the 8/30 + 8/15 + 8/0 (combined CC 8 mg) group (-10.5 mmHg, p < 0.0001) and the 4/30 + 4/15 (combined CC 4 mg) group (-9.1 mmHg, p = 0.0022) than in the 0/30 (CC 0 mg) group (-5.3 mmHg). HbA(1C) significantly decreased in the 8/30 + 4/30 + 0/30 (combined PIO 30 mg) group (-0.35%, p < 0.0001) and the 8/15 + 4/15 (combined PIO 15 mg) group (-0.15%, p < 0.0001) compared with the 8/0 (PIO 0 mg) group (0.35%). Urinary albumin excretion reduction seen with the 0/30 and the 8/0 groups was significantly enhanced by CC/PIO combination. Clinical significance of this renoprotective effect of CC/PIO combination therapy needs to be studied further. Prolonged combined use of CC/PIO did not increase adverse events. Drug-related adverse events were similar to those during clinical use of CC and PIO. CC/PIO combination therapy improved BP/glycemic control and was well tolerated for 52 weeks. Thus, CC/PIO combination therapy is useful in patients with hypertension and type 2 diabetes mellitus.


Improvement of Gas-Sensing Performance of Large-Area Tungsten Disulfide Nanosheets by Surface Functionalization.
Semiconducting two-dimensional (2D) transition metal dichalcogenides (TMDCs) are promising gas-sensing materials due to their large surface-to-volume ratio. However, their poor gas-sensing performance resulting from the low response, incomplete recovery, and insufficient selectivity hinders the realization of high-performance 2D TMDC gas sensors. Here, we demonstrate the improvement of gas-sensing performance of large-area tungsten disulfide (WS2) nanosheets through surface functionalization using Ag nanowires (NWs). Large-area WS2 nanosheets were synthesized through atomic layer deposition of WO3 followed by sulfurization. The pristine WS2 gas sensors exhibited a significant response to acetone and NO2 but an incomplete recovery in the case of NO2 sensing. After AgNW functionalization, the WS2 gas sensor showed dramatically improved response (667%) and recovery upon NO2 exposure. Our results establish that the proposed method is a promising strategy to improve 2D TMDC gas sensors.


The impact of self-reported psychological stress levels on changes to peripheral blood immune biomarkers in recreational marathon runners during training and recovery.
Marathon training is both physically and psychologically stressful, both of which can lead to altered immunity. The purpose of this study was to determine if the overall immunoregulatory changes associated with the physical stress of marathon training are affected by psychological stress. Nineteen recreational marathoners completed the Perceived Stress Scale (PSS), State-Trait Anxiety Inventory (STAI) and Penn State Worry Questionnaire (PSWQ), and had levels of T cell subpopulations and cytokine (IFNγ, IL4 and IL10) production determined 4 weeks before (baseline), 24-48 h before (prerace) and 1 week after (recovery) participation in a marathon. PSS scores decreased at the prerace visit compared to baseline and remained low at recovery. Compared to baseline, there were significant changes to numerous immune measures at the prerace visit, including decreases in Th1/Th2 ratio, Tc1/Tc2 ratio, Tr1 and Th3 cell populations as well as decreases in IFNγ/IL4 cytokine ratio and IL10 production. Most immune parameters had returned to near baseline values at the recovery visit. Higher levels of perceived stress, anxiety and worry exacerbated many of the alterations in immunity that were observed at the prerace visit. Higher levels of perceived stress and worry had significant effects on changes to Treg, IL4 production and the IFNγ/IL4 cytokine ratio. Stress had an additional impact on changes in IL10 production. High anxiety levels resulted in significant changes to Treg, Tr1 and Th3. These data suggest that recreational marathon runners with higher levels of psychological stress may be more at risk for the immune alterations that are common during periods of prolonged physical training.


The role of immunosuppression in squamous cell carcinomas arising in seborrheic keratosis.
Seborrheic keratoses (SK) are common skin neoplasms considered to be benign. Reports of associated squamous cell carcinoma arising within seborrheic keratosis (SCC-SK) have been described. To describe the histopathologic characteristics of SCC-SK and identify predisposing factors in formation of these rare lesions. There were 162 cases of SCC-SK in a span of a decade (2003-2014). All of the histopathologic specimens and medical records were reviewed. Data from these patients were compared to a control group with seborrheic keratosis who were matched by age, sex, and location of lesion from the same time period (n = 162). SCC-SK has the classic histopathologic features of SK, such as hyperkeratosis, parakeratosis, papillomatosis, and pseudohorn cysts. The areas of squamous cell carcinoma were characterized by areas of squamous dysplasia (100%), hypogranulosis (79.6%), squamous eddies (79.6%), solar elastosis (80.9%), and brown pigmentation (59.9%). Patients with a history of immunosuppression had an increased risk for developing SCC-SK (19% vs 3%; P < .01), particularly when inhibition was transplant-associated (10% vs 0%; P < .01). This was a single center, retrospective study. SCC-SK occurs more often in elderly men with a history of immunosuppression associated with organ transplants.


Bilateral carpal tunnel surgery in one operation: Retrospective study.
Carpal tunnel syndrome is the most common entrapment syndrome. The incidence of a bilateral condition varies between 22% and 87%. The aim of our study was to assess the level of satisfaction and the clinical outcomes in a group of patients operated on through a bilateral neurolysis on the median nerve in the carpal tunnel, in one operating session. This is a retrospective study involving patients with an electromyographic and clinical diagnosis of bilateral carpal tunnel syndrome. Patients were treated on an outpatient basis and the bilateral neurolysis was performed by endoscopy. The postoperative data was collected during consultation by a senior surgeon or during telephone interviews. Patients were asked to respond to a satisfaction questionnaire and the functional outcome was assessed through the Quick-Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) questionnaire. Twenty-nine patients with bilateral carpal tunnel syndrome were operated on in single operating sessions between January 2009 and January 2014. The average follow-up was 46 months. The average age at the time of the intervention was 45 years. Two patients were lost to follow-up, and 27 were able to be assessed. In relation to the clinical and functional outcomes, the average Quick-DASH score was 6.78 (ranges: 0-43.2). Twenty-five patients (92.5%) were satisfied with this simultaneous treatment and 26 patients (96%) would choose the same technique again. One-stage surgery in cases of bilateral carpal tunnel syndrome appears to constitute a benefit for the patient, the surgeon and the anaesthetist, but it is reserved for patients who request it and who are motivated by this type of intervention.


The Norwegian EUROPEP questionnaire for patient evaluation of general practice: data quality, reliability and construct validity.
The EUROPEP is a widely used international instrument to evaluate general practice care from the perspective of patients, but measurement properties including reliability at the GP level are not sufficiently documented. The objectives of this study were to assess the psychometric properties of the Norwegian version of the EUROPEP and estimate GP-level reliability for scales and items. Nine hundred patients consulting nine GPs at a medical centre in Norway were invited to complete the Norwegian EUROPEP at home following a recent consultation. We assessed item missing and ceiling effects and used factor analysis to assess the structure of the 23 items of the EUROPEP. Scales were tested for reliability and construct validity, while reliability at the GP level was tested for items and scales. Five hundred and fifty-seven patients (61.9%) returned the questionnaire. Seven of 23 items had missing responses >10% and 20% had high ceiling effects. Factor analysis identified two groups of questions that formed scales with satisfactory internal consistency reliability and validity. The clinical behaviour scale (12 items) and the organization of care scale (4 items) met the criterion of 0.7 for Cronbach's alpha. The GP-level reliability was >0.7 for both scales, but 9 of 23 items were below the criterion of 0.7. The study identified two scales in the Norwegian EUROPEP instrument with satisfactory psychometric properties. However, high proportions of item non-response large ceiling effects and low GP-level reliability for several items indicate the need for further instrument refinement.


Antihypertensive efficacy of Melothria maderaspatana leaf extract on sham-operated and uninephrectomized DOCA-salt hypertensive rats.
The plant Melothria maderaspatana (MME) has been used traditionally as antihypertensive and has been proven scientifically to possess high antioxidant and hepatoprotective activity. The present study has been designed to investigate the antihypertensive effect of ethanolic extract of MME leaves on sham-operated and uninephrectomized DOCA-salt-induced hypertensive male albino Wistar rats. A midscapular incision was made on each rat and the left kidney was excised after ligation of the renal artery. The surgical wound was closed using a suture. After one week recovery period, hypertension was induced by subcutaneous injection of DOCA-salt solution, twice a week, and the rats received a 1% sodium chloride solution as drinking water throughout the experimental period. After 6 weeks injection of DOCA-salt, systolic, diastolic and mean arterial blood pressure was significantly elevated as compared with sham-operated control. Treatment with MME significantly decreased theblood pressure. Thus, the results show that MME possesses antihypertensive activity in DOCA-salt hypertensive rats.


Staining for intracytoplasmic lumina and CAM5.2 increases the detection rate for bile duct cancers.
Endoscopic biopsies have a low sensitivity for diagnosing malignant bile duct strictures. Tumor markers detected by mucin staining and immunohistochemistry may help to determine the malignancy of a biopsy specimen where histologic evaluation alone is nondiagnostic. 61 patients who underwent forceps biopsies were retrospectively identified, yielding 49 and 40 biopsy specimens for strictures finally diagnosed as benign and malignant, respectively. Biopsy specimens were histologically evaluated and stained for p53, Ki-67, carcinoembryonic antigen (CEA), CA19-9, CAM5.2, and presence of intracytoplasmic lumina (ICL). Sensitivity, specificity, positive and negative predictive values (PPV and NPV), and positive and negative likelihood ratios (PLR and NLR) were calculated to evaluate the performance of each test. Histology alone provided sensitivity and specificity of 53 % and 100 %. Addition of ICL or CAM5.2 increased sensitivity to 73 % or 60 %, respectively, and provided excellent specificity, PPV, and PLR (ICL, 98 %, 97 %, and 36; CAM5.2, 100 %, 100 %, and infinite). Both stains in combination increased the sensitivity to 75 %. Staining for Ki-67, p53, CEA, and CA19-9 increased the sensitivity to detect malignancy (range 60 % to 83 %), but significantly reduced the specificity, PPV and PLR (ranges 73 % to 90 %, 72 % to 86 %, and 3 to 7, respectively). Markers in all combinations performed poorly as a negative test (NPV 69 % to 87 %, and NLR 0.19 to 0.55). Staining for tumor markers ICL and CAM5.2 can improve the diagnostic value of endoscopic biopsies, and may change the course of management for patients with indeterminate histological findings.


Study of antioxidant effects on malignant glioma cells by constructing a tumor-microvascular structure on microchip.
In this work, a three-dimensional tumor-microvascular structure was simulated on a microfluidic chip for study of antioxidants effects on malignant glioma cells in vitro. The 3D hydrogel containing lumen was constructed to co-culture endothelial cells and glioma cells to mimic tumor microvascular environment. Macroporous gelatin transglutaminase (TG) hydrogel was prepared with biological and mechanical properties suitable for cells culture and nutrient refresh. To reform a vessel structure, U87 cells were dispersed in the TG-gelatin hydrogel and HUVEC cells were seeded in the lumen of hydrogel. Three typical antioxidants (α-lipoic acid, catechins and ascorbic acid) have been selected to research the antioxidant effects of glioma cells in the simulative tumor microenvironment. The results showed that the HUVEC cells formed vessel presented the transportation and penetrable functions for antioxidants from lumen to glioma cells. The antioxidants displayed higher selectivity to U87 cells than HUVEC cells and α-lipoic acid has a strong antioxidant capacity.


Numerical simulation of endovenous laser treatment of the incompetent great saphenous vein with external air cooling.
Endovenous laser treatment (ELT) has been proposed as an alternative in the treatment of reflux of the great saphenous vein. Before the procedure, peri-saphenous subcutaneous tumescent saline solution infiltration is usually performed. However, diffusion of this tumescent fluid is rapidly observed and can potentially reduce the efficacy as a heat sink. External skin cooling with cold air was proposed as an alternative solution. The objective of this study is to compare endovenous laser treatment without and with air cooling by realistic numerical simulations. An optical-thermal damage model was formulated and implemented using finite element modeling. The general model simulated light distribution using the diffusion approximation of the transport theory, temperature rise using the bioheat equation, and laser-induced injury using the Arrhenius damage model. Parameters, used in clinical procedures, were considered: power, 15 W; pulse duration, 1 s; fiber pull back, 3-mm increments every second; cold air applied in continuous mode during ELT; and no tumescent anesthesia. Simulations were performed for vein locations at 5, 10, and 15 mm in depth, with and without air cooling. For a vein located at 15 mm in depth, no significant difference was observed with and without cooling. For a vein located at 10 mm in depth, surface temperature increase up to 45 °C is observed without cooling. For a vein located at 5 mm, without cooling, temperature increase leads to irreversible damage of dermis and epidermis. Conversely, with air cooling, surface temperature reaches a maximum of 38 °C in accordance with recordings performed on patients. ELT of the incompetent great saphenous vein with external air cooling system is a promising therapy technique. Use of cold air on the skin continuously flowing in the area of laser shot decreased significantly the heat extent and the thermal damage in the perivenous tissues and the skin.


Percutaneous radiofrequency ablation for treatment of giant cell tumor of bone guided by real-time US fused with CT.
Radiofrequency ablation (RFA) is a well-established technique for the treatment of soft tissue tumors of the liver and kidney that has increasingly been used for both benign and malignant bone tumors, such as giant cell tumor of bone (GCT). Reports in the literature pertaining to RFA for GCT have involved computed tomography (CT)-guided RFA, which presents several drawbacks such as radiation, lack of real-time monitoring, and the fact that it may be time-consuming. We report a case of GCT treated with percutaneous RFA using ultrasound guidance with CT fusion, which offers a simple, real-time guidance solution without radiation.


Neuronal intranuclear inclusion disease in identical twins.
A pair of female identical twins exhibited slurred speech, nystagmus, and oculogyral spasms starting at age 11. The patients then had episodic rage, extrapyramidal and lower motor neuron abnormalities, and grand mal seizures, but retained largely normal intelligence, until death at age 21. Severe loss of nigral and craniospinal motor neurons was noted postmortem. Round, eosinophilic, autofluorescent inclusion bodies, 3 to 10 microns in diameter, were observed in the nuclei of most nerve cell types of the central and peripheral nervous systems and retina. Ultrastructurally the inclusions appeared as masses of filaments without a limiting membrane, the constituent filaments having a diameter of 8.5 to 9.5 nm. Histochemical results suggested the presence of proteins with a high content of tryptophan. Four similar cases have been reported previously under various designations. We propose the name neuronal intranuclear inclusion disease for the disorder.


A 3D 12-ring zeolite with ordered 4-ring vacancies occupied by (H2O)2 dimers.
A germanate zeolite, PKU-14, with a three- dimensional large-pore channel system was structurally characterized by a combination of high-resolution powder X-ray diffraction, rotation electron diffraction, NMR, and IR spectroscopy. Ordered Ge4 O4 vacancies inside the [4(6) .6(12) ] cages has been found in PKU-14, in which a unique (H2 O)2 dimer was located at the vacancies and played a structure-directing role. It is the first time that water clusters are found to be templates for ordered framework vacancies.


Effects of primary chemotherapy in conservative treatment of breast cancer patients with operable tumors larger than 3 cm. Results of a randomized trial in a single centre.
272 women with operable breast adenocarcinomas larger than 3 cm were included in a randomized trial. The patients in group A (n = 138) with histological nodal involvement (N+) or a lack of estrogen and progesterone receptors (EPR-) were treated by initial mastectomy and axillary node dissection + adjuvant chemotherapy. Those in group B (n = 134) were treated by initial chemotherapy (the same as in group A) followed by loco-regional treatment, adjusted according to their response to chemotherapy. Prognostic factors were identical in the two groups. In group A, 32 patients received no adjuvant treatment (N- and EPR+), while 104 were given adjuvant chemotherapy (N+ and/or EPR-). Two patients were lost to follow-up. In group B, all patients received initial chemotherapy; 44 were in complete clinical remission and were treated with radiotherapy only; 40 with residual tumor (less than 20 mm) were treated with tumorectomy + axillary node dissection + radiotherapy; 49 with residual tumors (greater than 20 mm) had mastectomies. Conservative treatment was administered to 84 patients in group B (62.6%). EPR-tumors responded better to chemotherapy than did EPR+ ones (p = .003). After a median follow-up of 34 months, isolated local recurrences were more frequent in the group with initial chemotherapy, which, however, experienced a better overall survival (p = 0.04).