Lung cancer staging now and in the future.
For a long time lung cancer was associated with a fatalistic approach by healthcare professionals. In recent years, advances in imaging, improved diagnostic techniques and more effective treatment modalities are reasons for optimism. Accurate lung cancer staging is vitally important because treatment options and prognosis differ significantly by stage. The staging algorithm should include a contrast computed tomography (CT) of the chest and the upper abdomen including adrenals, positron emission tomography/CT for staging the mediastinum and to rule out extrathoracic metastasis in patients considered for surgical resection, endosonography-guided needle sampling procedure replacing mediastinoscopy for near complete mediastinal staging, and brain imaging as clinically indicated. Applicability of evidence-based guidelines for staging of lung cancer depends on the available expertise and level of resources and is directly impacted by financial issues. Considering the diversity of healthcare infrastructure and economic performance of Asian countries, optimal and cost-effective use of staging methods appropriate to the available resources is prudent. The pulmonologist plays a central role in the multidisciplinary approach to lung cancer diagnosis, staging and management. Regional respiratory societies such as the Asian Pacific Society of Respirology should work with national respiratory societies to strive for uniform standards of care. For developing countries, a minimum set of care standards should be formulated. Cost-effective delivery of optimal care for lung cancer patients, including staging within the various healthcare systems, should be encouraged and most importantly, tobacco control implementation should receive an absolute priority status in all countries in Asia.


Insulin-lowering agents in the management of polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a medical condition that has brought multiple specialists together. Gynecologists, endocrinologists, cardiologists, pediatricians, and dermatologists are all concerned with PCOS patients and share research data and design clinical trials to learn more about the syndrome. Insulin resistance is a common feature of PCOS and is more marked in obese women, suggesting that PCOS and obesity have a synergistic effect on the magnitude of the insulin disorder. Hyperinsulinemia associated with insulin resistance has been causally linked to all features of the syndrome, such as hyperandrogenism, reproductive disorders, acne, hirsutism, and metabolic disturbances. Women with PCOS should be evaluated for cardiovascular risk factors, such as lipid profile and blood pressure. Modification of diet and lifestyle should be suggested to those who are obese. Several insulin-lowering agents have been tested in the management of PCOS. In particular, metformin is the only drug currently in widespread clinical use for treatment of PCOS. In a high percentage of patients, treatment with metformin is followed by regularization of menstrual cycle, reduction in hyperandrogenism and in cardiovascular risk factors, and improvement in response to therapies for induction of ovulation.


Recombinant protein delivery enables modulation of the phototransduction cascade in mouse retina.
Inherited retinal dystrophies are often associated with mutations in the genes involved in the phototransduction cascade in photoreceptors, a paradigmatic signaling pathway mediated by G protein-coupled receptors. Photoreceptor viability is strictly dependent on the levels of the second messengers cGMP and Ca2+. Here we explored the possibility of modulating the phototransduction cascade in mouse rods using direct or liposome-mediated administration of a recombinant protein crucial for regulating the interplay of the second messengers in photoreceptor outer segments. The effects of administration of the free and liposome-encapsulated human guanylate cyclase-activating protein 1 (GCAP1) were compared in biological systems of increasing complexity (in cyto, ex vivo, and in vivo). The analysis of protein biodistribution and the direct measurement of functional alteration in rod photoresponses show that the exogenous GCAP1 protein is fully incorporated into the mouse retina and photoreceptor outer segments. Furthermore, only in the presence of a point mutation associated with cone-rod dystrophy in humans p.(E111V), protein delivery induces a disease-like electrophysiological phenotype, consistent with constitutive activation of the retinal guanylate cyclase. Our study demonstrates that both direct and liposome-mediated protein delivery are powerful complementary tools for targeting signaling cascades in neuronal cells, which could be particularly important for the treatment of autosomal dominant genetic diseases.


Site of alpha blockade in the demonstration of nonvagally mediated gastric acid secretion.
Results of previous reports from this laboratory have indicated that electrical centripetal vagal stimulation in the dog that has a bilateral vagotomy evokes mucus secretion from the pyloric antrum and produces an inhibition of motor activities from the stomach to the terminal ileum. We have subsequently observed that electrical central vagal stimulation after the administration of the alpha adrenolytic, phenoxybenzamine to these preparations results in general augmentation of gastrointestinal motor activity. It was also determined that electrical central vagal stimulation, using the same stimulus parameters that were stimulatory for mucus secretion, now resulted in significant increases in both volume and titratable acid secretions. The intact arterial pressor response during periods of electrical central vagal stimulation which enhanced gastric acid output in the dog that had a bilateral vagotomy eliminates the possibility that the mechanism of acid release involves the necessary suppression of the systemic pressor reflex. It is further concluded that the acid-enhancing effect of phenoxybenzamine appears to be limited to the pyloric antrum, even though the acid is secreted from the corpus. This suggests that the neural portion of the acid effect is confined to the antrum. We have successfully demonstrated that the acid-enhancing reflex effect is associated with a definite rise in the concentration of circulating gastrin.


Trastuzumab and vinorelbine as highly effective and safe therapy for HER-2-overexpressing metastatic breast cancer. A single institution experience.
Trastuzumab-based therapy has improved survival of women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. From September 2002 to July 2006, 45 women with metastatic breast cancer HER2 3+, or 2+ and positive for HER2 gene amplification, were enrolled in the study and received a combination therapy with vinorelbine, 25 mg/m2 weeks 1 and 2, plus trastuzumab, 4 mg/kg loading dose and then 2 mg/kg weekly, in a three weeks cycle. Eligibility criteria included measurable disease and a baseline ejection fraction > or = 50%. Forty-two percent of the patients were not pretreated, whereas 58% had received a previous chemotherapy regimen for metastatic disease, including anthracyclines and/or taxanes (47%), and trastuzumab plus taxol (11%). We observed 14 (31%) complete responses and 21 (47%) partial responses, with an overall response rate of 78%. Stable disease > 6 months was assessed for 5 (11%) patients with a clinical benefit of 89%. Five (11%) patients progressed. With a median follow-up of 11 months, median time to progression was 9 months and median duration of response was 7.6 months for complete remissions and 4 months for partial remissions. Median survival was 29 months. In spite of a smaller dose intensity of vinorelbine than previously reported, the regimen evaluated was notably effective in terms of response rate, time to progression and survival, with very mild toxicity.


Troxerutin Stimulates Osteoblast Differentiation of Mesenchymal Stem Cell and Facilitates Bone Fracture Healing.
Troxerutin (TRX), a semi-synthetic derivative of the natural bioflavonoid rutin, is a bioactive flavonoid widely abundant in various fruits and vegetables. Known as vitamin P4, TRX has been demonstrated to have several activities including anti-inflammation, anti-oxidants, vasoprotection, and immune support in various studies. Although rutin, the precursor of troxerutin, was reported to have a protective role against bone loss, the function of TRX in skeletal system remains unknown. In the present study, we found that TRX promoted osteogenic differentiation of human mesenchymal stem cells (MSCs) in a concentration-dependent manner by stimulating the alkaline phosphatase (ALP) activity, calcium nodule formation and osteogenic marker genes expression in vitro. The further investigation demonstrated that TRX stimulated the expression of the critical transcription factor β-catenin and several downstream target genes of Wnt signaling, thus activated Wnt/β-catenin signaling. Using a femur fracture rats model, TRX was found to stimulate new bone formation and accelerate the fracture healing in vivo. Collectively, our data demonstrated that TRX could promote osteogenesis in vitro and facilitate the fracture healing in vivo, indicating that TRX may be a promising therapeutic candidate for bone fracture repair.


An improved reservoir for the flushing test to diagnose shunt insufficiency.
OBJECTIVE Reservoirs integrated into hydrocephalus shunts are commonly used for the removal of CSF and for intra-ventricular pressure measurement. Pumping with the reservoir to diagnose shunt sufficiency is still a matter of controversy. The authors describe an improved flushing device and its characteristic features in vitro and in vivo. METHODS The flushing reservoir is constructed with a sapphire ball in a cage as a nonresistance valve to also enable the detection of distal occlusions. The most important reservoir parameters were investigated in vitro, simulating total and partial proximal and distal shunt occlusions. Then the expected advantages were assessed in vivo by evaluating the pump test data of 360 implanted reservoirs. The results were compared with those found in the literature. RESULTS The optimization of the technical parameters of the device, such as the high stroke volume in combination with moderate suction force, are obvious advantages compared with other flushing devices. Total occlusion of the ventricular catheter and the valve could be assessed with high certainty. The detection of a total obstruction of the peritoneal catheter or any partial obstruction is also possible, depending on its exact grade and location. CONCLUSIONS Shunt obstructions can be assessed using the pumping test. The reservoir construction presented here provides a clear enhancement of that diagnostic test.


Capillary-wall collagen as a biophysical marker of nanotherapeutic permeability into the tumor microenvironment.
The capillary wall is the chief barrier to tissue entry of therapeutic nanoparticles, thereby dictating their efficacy. Collagen fibers are an important component of capillary walls, affecting leakiness in healthy or tumor vasculature. Using a computational model along with in vivo systems, we compared how collagen structure affects the diffusion flux of a 1-nm chemotherapeutic molecule [doxorubicin (DOX)] and an 80-nm chemotherapy-loaded pegylated liposome (DOX-PLD) in tumor vasculature. We found a direct correlation between the collagen content around a tumor vessel to the permeability of that vessel permeability to DOX-PLD, indicating that collagen content may offer a biophysical marker of extravasation potential of liposomal drug formulations. Our results also suggested that while pharmacokinetics determined the delivery of DOX and DOX-PLD to the same tumor phenotype, collagen content determined the extravasation of DOX-PLD to different tumor phenotypes. Transport physics may provide a deeper view into how nanotherapeutics cross biological barriers, possibly helping explain the balance between biological and physical aspects of drug delivery.


NAD+ metabolite levels as a function of vitamins and calorie restriction: evidence for different mechanisms of longevity.
NAD+ is a coenzyme for hydride transfer enzymes and a substrate for sirtuins and other NAD+-dependent ADPribose transfer enzymes. In wild-type Saccharomyces cerevisiae, calorie restriction accomplished by glucose limitation extends replicative lifespan in a manner that depends on Sir2 and the NAD+ salvage enzymes, nicotinic acid phosphoribosyl transferase and nicotinamidase. Though alterations in the NAD+ to nicotinamide ratio and the NAD+ to NADH ratio are anticipated by models to account for the effects of calorie restriction, the nature of a putative change in NAD+ metabolism requires analytical definition and quantification of the key metabolites. Hydrophilic interaction chromatography followed by tandem electrospray mass spectrometry were used to identify the 12 compounds that constitute the core NAD+ metabolome and 6 related nucleosides and nucleotides. Whereas yeast extract and nicotinic acid increase net NAD+ synthesis in a manner that can account for extended lifespan, glucose restriction does not alter NAD+ or nicotinamide levels in ways that would increase Sir2 activity. The results constrain the possible mechanisms by which calorie restriction may regulate Sir2 and suggest that provision of vitamins and calorie restriction extend lifespan by different mechanisms.


Mechanism of inactivation of trypsin by antithrombin.
General aspects of the mechanism of antithrombin action were elucidated by a comparison of the inactivation of trypsin by antithrombin with the inactivation of coagulation proteinases by the inhibitor. Bovine antithrombin and bovine trypsin were shown to form an inactive equimolar complex. A non-complexed, proteolytically modified form of antithrombin, electrophoretically identical with that formed in the reaction with coagulation proteinases, was also produced in the reaction with trypsin. In the absence of heparin, the inactivation of trypsin by antithrombin was 20 times faster than the inactivation of thrombin; the second-order rate constant was 1.5 x 10(5)m(-1).s(-1) at 25 degrees C and pH 7.4. However, the inhibition of thrombin was accelerated about 30 times more efficiently by small amounts of heparin than was trypsin inhibition. Dissociation of the antithrombin-trypsin complex at pH 7.4 followed first-order kinetics with a half-life for the complex of about 80h at 25 degrees C. The complex was rapidly and quantitatively dissociated at pH 11, resulting in the liberation of a modified two-chain form of the inhibitor, cleaved at the same Arg-Ser bond as in modified antithrombin released from complexes with thrombin, Factor Xa and Factor IXa. This supports the previous proposal that this bond is the active-site bond of antithrombin. Antisera specific for thrombin-modified antithrombin reacted with purified antithrombin-trypsin complex, indicating that the inhibitor was present in the complex in a form immunologically identical with thrombin-modified antithrombin. The results thus suggest a common mechanism, but different kinetics, for the inhibition of trypsin and coagulation proteinases by antithrombin.


The influence of the beam modulation technique on dose and RBE in proton radiation therapy.
Because a dose can be described as fluence times LET, it is evident that, in a mixed radiation field, similar doses can be achieved with different particle energy distributions. Isodose contours are iso-effect contours only if the energy spectra of the accompanying particles remain constant. Under this condition, the beam delivery technique used to build a spread-out Bragg peak (SOBP) can influence the relative biological effectiveness (RBE). We investigated the influence of the beam modulation method on the dose distribution and, taking into account the respective RBEs, on the biological dose distribution. For this, we first performed proton transport calculations in order to obtain the dose and the proton energy spectra at a given depth. Secondly, RBE values were calculated using the microdosimetric response function and the track structure model for two biological end points. We found an increasing RBE with depth within the SOBP. The higher the energy used for modulation the lower the average LET and the RBE and the higher the proton fluence. The RBE for an active beam modulation system behaves like the respective RBE of a passive system with similar initial beam energy.


Circulating particles during cardiac surgery.
Shed blood is known to be a source of lipid micro-emboli in cardiac surgery. The aim of this study was to characterize the occurrence of these particles at different stages of the operation, and to study their occurrence in the circulation at multiple time-points after the retransfusion of shed blood. Forty-four patients undergoing routine surgery with cardiopulmonary bypass were included. Blood was sampled from the surgical field at different sampling locations during the operation. Shed blood was collected in a transfusion bag and retransfused. After which, blood was sampled from the arterial line of the heart-lung machine. A Coulter counter was used for particle determinion. The mean volume of shed blood collected was 340+/-215 ml. Particles in the size range 10-60 microm were found at varying concentrations, with the highest concentrations being found in blood collected after cannulation and from the pleura. After retransfusion of this blood, a biphasic response was seen in the blood drawn from the efferent line of the heart-lung machine. Particles are found in shed blood at all times during cardiac surgery, and when this blood was retransfused an increase was seen in particle concentration in the heart-lung machine.


Segmental pigmentation disorder: A rare form of cutaneous dyspigmentation.
Segmental pigmentation disorder (SegPD) is a rare type of cutaneous dyspigmentation. This hereditary disorder, first described some 20 years ago, is characterized by hypo and hyperpigmented patches on the trunk, extremities and less likely on the face and neck. These lesions are considered as a type of checkerboard pattern. Herein, we present a 26-year-old male who presented with hyperpigmented patches on his trunk, neck and upper extremities. Considering the clinical and histopathological findings, the diagnosis of SegPD was confirmed. SegPD is a somewhat neglected entity which should be considered in differential diagnosis of pigmentation disorders.


Petri Net modelling approach for analysing the behaviour of Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ signalling pathways in arrhythmogenic right ventricular cardiomyopathy.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure and sudden death. The hallmark pathological findings are progressive myocyte loss and fibro fatty replacement, with a predilection for the right ventricle. This study focuses on the adipose tissue formation in cardiomyocyte by considering the signal transduction pathways including Wnt/[inline-formula removed]-catenin and Wnt/Ca2+ regulation system. These pathways are modelled and analysed using stochastic petri nets (SPN) in order to increase our comprehension of ARVC and in turn its treatment regimen. The Wnt/[inline-formula removed]-catenin model predicts that the dysregulation or absence of Wnt signalling, inhibition of dishevelled and elevation of glycogen synthase kinase 3 along with casein kinase I are key cytotoxic events resulting in apoptosis. Moreover, the Wnt/Ca2+ SPN model demonstrates that the Bcl2 gene inhibited by c-Jun N-terminal kinase protein in the event of endoplasmic reticulum stress due to action potential and increased amount of intracellular Ca2+ which recovers the Ca2+ homeostasis by phospholipase C, this event positively regulates the Bcl2 to suppress the mitochondrial apoptosis which causes ARVC.


Socioeconomic status and health-related quality of life among adults and older with overactive bladder.
To study the effect of socioeconomic status (SES) on health-related quality of life (HRQoL) among persons with overactive bladder (OAB). A randomized HRQoL study was conducted from the year 2014 until the year 2016 based on the OAB pathology department of the regional clinical diagnostics center. The medical institutions where the study was conducted had outpatient care. The simple response frequency was 81%. A total of 1893 men and women with OAB aged 35-85 (average 58.3 years) were selected by blind random sampling. Included into the group of examined individuals were persons who diagnosis provided after the examination was OAB. Evaluation of HRQoL was conducted using the SF-6D questionnaire. The OAB diagnosis was confirmed using the OAB-questionnaire and uroflowmetry. We hypothesized that the impact of SES on the HRQoL of patients with OAB has significant features. Described for the first time were HRQoL measures in various SES levels within different ages of people suffering from OAB. The strongest relationship was identified between education level, professional activity and HRQoL measures; meanwhile the weakest relationship was between income and HRQoL measures. We also confirmed the efficiency of evaluating HRQoL while using SF-6D and SRH as an external standard. The improvement of HRQoL in persons with OAB is contingent upon increment in their level of awareness about the methods of OAB treatment and the effectiveness of treatment for severe symptoms of LUT pathology, increased social support and, possibly, physical activity.


A seven-year experience with methicillin-resistant Staphylococcus aureus.
From July 1983 through June 1990, 319 patients with methicillin-resistant Staphylococcus aureus (MRSA) were identified at the University of California, Davis Medical Center. Initially, our goal was eradication of MRSA from the hospital flora. Our approach was: (a) immediate notification of all MRSA isolates by the microbiology laboratory; (b) strict isolation; (c) cohorting; (d) bathing patients with an iodophor; (e) surveillance cultures of patients and staff; (f) treatment of all colonized persons; and (g) strict isolation on readmission. Control of spread was achieved but eradication was not. In 1987 our strategy was modified in order to establish the least restrictive methods to maintain control of the spread of MRSA. After notification by the microbiology laboratory, we now require: (a) contact isolation; (b) surveillance cultures of patients associated with each new case; and (c) contact isolation for all MRSA patients on readmission. Strict isolation and employee culturing are used only during major outbreaks. We have averaged four new cases of MRSA per month over the 7-year period, including four major outbreaks. Since 1987, we have averaged only three new cases per month with one major MRSA outbreak. Annual cost savings of greater than $50,000 have been realized through the policy modifications. We conclude that the use of contact isolation with some modifications has saved time and money and has successfully controlled the spread of MRSA in our university hospital.


The bioactivity of Hedysarum coronarium extracts on skin enzymes and cells correlates with phenolic content.
The search for bioactive compounds from botanical sources is attracting much interest. However, differences in chemical composition may occur within the same species depending on different geographical origins. We evaluated the properties on skin enzymes and cells of extracts from sulla legume crop Hedysarum coronarium L. (Fabaceae), collected at two Italian sites near Pisa and Ventimiglia, for possible dermatological and cosmetic applications. Plant aerial portions were extracted in MTBE/ethyl acetate/acetone, obtaining two extracts named Pisa sulla extract (PSE) and Ventimiglia sulla extract (VSE). Extracts were subjected to chemical characterization, LC-MS/MS analysis and biological assays. PSE showed stronger antiradical scavenging and higher phenolic and flavonoid contents with respect to VSE. LC-MS/MS analysis revealed similar composition for the two extracts, but PSE was richer in condensed tannins and flavonoids, principally rhoifolin, quercetin, naringenin and derivatives. PSE induced stronger inhibition on collagenase and elastase by in vitro enzyme assays, possibly due to higher levels of condensed tannins and quercetin. ELISA bioassay on human dermal fibroblasts revealed stronger PSE induction of collagen production. Determination of glycerol release from adipocytes disclosed stronger stimulation of lipolysis by PSE, allegedly ascribed to higher charge of quercetin and derivatives. In summary, the higher richness in phenolics of PSE is strictly related to stronger bioactivity. Data indicate that aerial H. coronarium material is suitable for the development of dermatological and cosmeceutical products, but the geographical origin is an important factor for maximally exploiting the biological properties of this species.


Effectiveness of the CANRISK tool in the identification of dysglycemia in a Canadian South Asian Population.
South Asians have a higher than average risk of developing type 2 diabetes. We ascertained the effectiveness of CANRISK, an existing diabetes risk assessment tool, examining its sensitivity and specificity at two different predetermined scoring cut-off points comparing those participants under the age of 40 and those 40 and over. We examined the predictive ability of a model based on CANRISK variables, comparing ethno-specific body mass index (BMI) and waist circumference (WC) cut-off points with the original BMI and WC cut-off points to see if predictive ability could be improved for this population. Canadian South Asians of unknown diabetes status, age 18 to 78, were recruited across seven provinces from various community or health centers. CANRISK variables were collected followed by oral glucose tolerance testing. Descriptive analysis, logistic regression including alternative ethno-specific BMI and WC cut-off points, and sensitivity and specificity analyses were performed. 832 participants were recruited (584 under age 40). Using the entire study sample, logistic regression models including CANRISK variables predicted dysglycemia effectively (AUC of 0.80). However, by using alternative BMI/WC cut-off points with the scoring algorithm, predictive power via AUC was not improved. Sensitivity and specificity of CANRISK using the original pre-determined "high risk" cut-off point of 33 points in individuals age 40 years or over were 93% and 35%, respectively; in individuals under 40, these were 33% and 92%, respectively. Using the lower pre-determined "moderate risk" cut-off point of 21 points improved the sensitivity to 77% and specificity to 53% in the younger age group. The existing CANRISK is an adequate risk assessment tool for dysglycemia in Canadian South Asians for those age 40 years and over; however, the tool does not work as well for individuals under 40. The lower cut-off of 21 points may be warranted for younger individuals to minimize false negatives. Ethno-specific BMI/WC cutoff points did not improve predictive ability of the CANRISK scoring algorithm as measured by AUC.


Purification and partial characterization of a 17 beta-estradiol-binding macromolecule in the human pancreas.
Studies have been performed in order to investigate the presence of estrogen-binding proteins in the human pancreas that may provide the biochemical basis for tissue-specific treatment of pancreatic carcinoma with estrogen-based cytotoxic drugs. Using in vitro techniques, an estrogen-binding macromolecule has been purified from pancreatic cytosol. With estradiol a ligand, Kd was calculated to be 1.7 X 10(-7) M, and this protein was found to constitute about 4% of the total protein content in the cytosol. No metabolism of estradiol was detected under the in vitro conditions used. Competition experiments indicated that, besides estradiol, the protein also had some affinity for estrone and estriol but not for testosterone, progesterone, or dexamethasone. The protein was purified to homogeneity using chromatography on concanavalin A and hydroxylapatite followed by preparative polyacrylamide gel electrophoresis. The purified protein, still able to bind, [3H]-estradiol, gave one single protein-staining band when analyzed using different electrophoretic systems. The steroid-protein and did not bind to phosphocellulose or DNA-cellulose and did not show any similarities to steroid receptor proteins. The complex has a Strokes' radius of 52 A and a sedimentation coefficient of 3S. The biological significance of the macromolecule is known, but the protein is probably synthesized in the pancreas since no similar protein could be detected in serum. Studies are now being carried out to investigate whether this novel protein in the human pancreas may interact with complexes between cytotoxic agents and estrogens and provide the basis for tissue-specific treatment of pancreatic carcinoma.


Rheumatoid arthritis and personality: a controlled study.
Evidence in support of claims for the existence of a special relationship between personality and rheumatoid arthritis is conflicting. In this study four groups-one of patients with early rheumatoid arthritis, one of patients with chronic rheumatoid arthritis, one of neurotic patients, and a normal control group-were compared by means of the Maudsley Personality Inventory (M.P.I.) and a neurotic trait in childhood (N.T.C.) score. Both arthritis groups had a lower M.P.I. neuroticism score than the normal control group, with greater significance in the chronic arthritis group. The neurotic group had a significantly higher neuroticism score than the other three groups. Both arthritis groups had a lower extraversion score than normal controls, again with greater significance in the chronic arthritis group. The neurotic group scored significantly less than normal controls on the extraversion scale and intermediately between the early and chronic arthritis groups. There was no significant difference between the arthritis groups and the normal control group in the N.T.C. score, but it was significantly increased in the neurotic group.These findings suggest that people with rheumatoid arthritis differ significantly in personality from normal and from neurotic people, that the differences are accentuated with chronicity in the rheumatoid process, and that the differences develop as a result of the arthritis.


Impact of electrostatics in redox modulation of oxidative stress by Mn porphyrins: protection of SOD-deficient Escherichia coli via alternative mechanism where Mn porphyrin acts as a Mn carrier.
Understanding the factors that determine the ability of Mn porphyrins to scavenge reactive species is essential for tuning their in vivo efficacy. We present herein the revised structure-activity relationships accounting for the critical importance of electrostatics in the Mn porphyrin-based redox modulation systems and show that the design of effective SOD mimics (per se) based on anionic porphyrins is greatly hindered by inappropriate electrostatics. A new strategy for the beta-octabromination of the prototypical anionic Mn porphyrins Mn(III) meso-tetrakis(p-carboxylatophenyl)porphyrin ([Mn(III)TCPP](3-) or MnTBAP(3-)) and Mn(III) meso-tetrakis(p-sulfonatophenyl)porphyrin ([Mn(III)TSPP](3-)), to yield the corresponding anionic analogues [Mn(III)Br(8)TCPP](3-) and [Mn(III)Br(8)TSPP](3-), respectively, is described along with characterization data, stability studies, and their ability to substitute for SOD in SOD-deficient Escherichia coli. Despite the Mn(III)/Mn(II) reduction potential of [Mn(III)Br(8)TCPP](3-) and [Mn(III)Br(8)TSPP](3-) being close to the SOD-enzyme optimum and nearly identical to that of the cationic Mn(III) meso-tetrakis(N-methylpyridinium-2-yl)porphyrin (Mn(III)TM-2-PyP(5+)), the SOD activity of both anionic brominated porphyrins ([Mn(III)Br(8)TCPP](3-), E(1/2)=+213 mV vs NHE, log k(cat)=5.07; [Mn(III)Br(8)TSPP](3-), E(1/2)=+209 mV, log k(cat)=5.56) is considerably lower than that of Mn(III)TM-2-PyP(5+) (E(1/2)=+220 mV, log k(cat)=7.79). This illustrates the impact of electrostatic guidance of O(2)(-) toward the metal center of the mimic. With low k(cat), the [Mn(III)TCPP](3-), [Mn(III)TSPP](3-), and [Mn(III)Br(8)TCPP](3-) did not rescue SOD-deficient E. coli. The striking ability of [Mn(III)Br(8)TSPP](3-) to substitute for the SOD enzymes in the E. coli model does not correlate with its log k(cat). In fact, the protectiveness of [Mn(III)Br(8)TSPP](3-) is comparable to or better than that of the potent SOD mimic Mn(III)TM-2-PyP(5+), even though the dismutation rate constant of the anionic complex is 170-fold smaller. Analyses of the medium and E. coli cell extract revealed that the major species in the [Mn(III)Br(8)TSPP](3-) system is not the Mn complex, but the free-base porphyrin [H(2)Br(8)TSPP](4-) instead. Control experiments with extracellular MnCl(2) showed the lack of E. coli protection, indicating that "free" Mn(2+) cannot enter the cell to a significant extent. We proposed herein the alternative mechanism where a labile Mn porphyrin [Mn(III)Br(8)TSPP](3-) is not an SOD mimic per se but carries Mn into the E. coli cell.


TMA Navigator: Network inference, patient stratification and survival analysis with tissue microarray data.
Tissue microarrays (TMAs) allow multiplexed analysis of tissue samples and are frequently used to estimate biomarker protein expression in tumour biopsies. TMA Navigator (www.tmanavigator.org) is an open access web application for analysis of TMA data and related information, accommodating categorical, semi-continuous and continuous expression scores. Non-biological variation, or batch effects, can hinder data analysis and may be mitigated using the ComBat algorithm, which is incorporated with enhancements for automated application to TMA data. Unsupervised grouping of samples (patients) is provided according to Gaussian mixture modelling of marker scores, with cardinality selected by Bayesian information criterion regularization. Kaplan-Meier survival analysis is available, including comparison of groups identified by mixture modelling using the Mantel-Cox log-rank test. TMA Navigator also supports network inference approaches useful for TMA datasets, which often constitute comparatively few markers. Tissue and cell-type specific networks derived from TMA expression data offer insights into the molecular logic underlying pathophenotypes, towards more effective and personalized medicine. Output is interactive, and results may be exported for use with external programs. Private anonymous access is available, and user accounts may be generated for easier data management.


[Significance of computerized tomography in the diagnosis of post-traumatic proximal carpal instability].
Proximal carpal instability is a painful condition characterized by early or late loss of radioulnar joint (RUJ) congruence not affecting the normal bone alignment of the two carpal rows. The joint incongruence or (incomplete) dislocation which leads to proximal instability is caused by many traumatic and nontraumatic events. The diagnosis of (incomplete) dislocation of the distal RUJ may be extremely difficult to make at conventional radiography because such injuries can be seen only when the lateral joint projection is perfect; otherwise the diagnosis is not reliable. CT is the only imaging tool diagnosing the grade of distal RUJ congruence independent of the examination technique. We studied the radiocarpal complex conditions leading to proximal instability at the Rizzoli Orthopedic Institute from December, 1995, through December, 1997. In all, 389 cases were seen, 376 from trauma and 13 of nontraumatic origin. Each injury was studied with conventional radiography, CT, and MRI. Radiography was performed in two projections, namely the posteroanterior one with hand extension and the lateral one with the forearm in neutral position and the elbow bent at 90 degrees; the projections were repeated whenever a cast brace was applied. Unenhanced CT was performed for comparison with the patient prone and the forearm and wrist in prone and neutral position, as well as with the patient, forearm and wrist supine. Three criteria of electronic image processing were adopted for the RUJ studies in the 3 projections: radioulnar lines, congruence, and epicenter. MRI was always performed after conventional radiography and CT. Only the involved radiocarpal region was studied; coronal, axial and sagittal images were acquired with T2-weighted GE and T1-weighted SE sequences. Proximal instability was found in 17 of 389 patients; it was early in 13 and late in 4 of them. The comparison of radiographic and CT results showed that the former method is unreliable, with 53% false negatives. Pain, a cast brace, congenital or acquired deformities of distal radius and ulna and patient mispositioning by the radiology technician can change the rotation of the forearm, wrist and hand and make a perfect laterolateral projection in neutral position unfeasible, which affects the radiographic diagnosis. Conversely, CT showed its extreme efficacy in assessing the distal RUJ congruence with no false negatives independent of the RUJ rotation and of instability type and grade. Conventional radiography is a poorly reliable tool for the diagnosis of joint incongruence and its grade. In contrast, CT can diagnose a RUJ (incomplete) dislocation easily and unquestionably, thanks to its axial capabilities, even when adequate radiographic studies would be unfeasible. If the anteroposterior projection of the radiocarpal complex shows a congenital or acquired deformity of distal radius, the lateral projection can be skipped and a CT scan in prone, neutral and supine position performed. The 3 CT criteria quantify incongruence type and grade, and also demonstrate the position of maximum incongruence and its decrease by position. The comparative study of the radiocarpal region makes CT a very useful and valuable tool in congenital instability because its allows the assessment of contralateral radioulnar congruence too. MRI is very useful in the diagnosis of injury or degeneration of the fibrocartilage complex, namely in patients with no bone changes at conventional radiography.


Phylogenetic analysis of members of the genus Rickettsia using the gene encoding the outer-membrane protein rOmpB (ompB).
To confirm the phylogenetic analysis previously inferred by comparison of the citrate synthase and rOmpA gene sequences (gitA and ompA, respectively), the rOmpB gene (ompB) of 24 strains of the genus Rickettsia was amplified and sequenced. rOmpB is an outer-membrane protein of high molecular mass, the presence of which can be demonstrated in most rickettsiae by immunological cross-reactivity in Western blots. No PCR amplification was obtained with Rickettsia bellii or Rickettsia canadensis. For the other rickettsiae, phylogenetic analysis was inferred from the comparison of both the gene and derived protein sequences by using parsimony, maximum-likelihood and neighbour-joining methods which gave the same organization. All nodes were well supported (>86% bootstrap values), except in the cluster including Rickettsia africae strain S and Rickettsia parkeri, and this analysis confirmed the previously established phylogeny obtained from combining results from gltA and ompA. Based on phylogenetic data, the current classification of the genus Rickettsia is inappropriate, specifically its division into two groups, typhus and spotted fever. Integration of phenotypic, genotypic and phylogenetic data will contribute to the definition of a polyphasic taxonomy as has been done for other bacterial genera.


Health impact of small-community water supply reliability.
There is still debate and uncertainty in the literature about the health benefits of community water supply interventions. This paper reports on a changing incidence of self-reported diarrhoea associated with the implementation of two community water supplies. We conducted prospective weekly recording of diarrhoeal disease in three communities. Two of the communities were scheduled to receive an improved water supply and one was expected to continue to rely on an unimproved source during the study period. Data of self-reported diarrhoea was collected from each participating household on a weekly basis for up to 56 weeks, of which some 17 weeks were prior to implementation of the new water supply systems. Data was modelled using Generalized Estimating Equations (GEE) to account for possible clustering within households and within villages. For the two intervention communities in the study, the incidence rate ratio (IRR) for all ages after the intervention was 0.43 (95% CI 0.24-0.79) when compared to the control community (who did not receive an intervention), implying a 57% reduction of diarrhoea. Both of the new water systems were unreliable, one not operating on 4 weeks and the other on 16 weeks. The more reliable of the two intervention systems was also associated with less illness than in the least reliable system (IRR=0.41, 95% CI 0.21-0.80). We also noted anecdotal reports that during supply failures in the new systems some people were starting to use household water treatment. The implementation of improved water systems does appear to have been associated with a reduction of diarrhoeal disease in the communities. However the health impact was most obvious in the community with the more reliable system. Further research needs to be done to determine whether public health gains from community water supply interventions can be leveraged by occasional use of household water treatment (HWT) during supply failures.


Crocin reduces the inflammation response in rheumatoid arthritis.
This study is to determine the role and mechanism of crocin in rheumatoid arthritis (RA). Totally 60 Wistar SD rats were randomly divided into control group, RA model group, methotrexate group, crocin high dose, middle dose, and low dose groups. The paw swelling degree, arthritis score, thymus and spleen index, the mRNA and protein levels of iNOS, and the serum content of TNF-α, IL-1β, and IL-6 were evaluated. Crocin treatment significantly alleviated the paw swelling of RA rats. The arthritis score in crocin treatment groups was significantly lower than that in RA model group. Additionally, the thymus index, but not the spleen index, declined remarkably in crocin treatment groups than in RA model group. Besides, crocin administration significantly reduced the iNOS production and the serum content of TNF-α, IL-1β, and IL-6. Crocin may exert potent anti-RA effects through inhibiting cytokine.


Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium.
The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.


Detection of human papillomavirus in organs of upper genital tract in women with cervical cancer.
In this study, we evaluated the presence of human papillomavirus (HPV) DNA in organs of the female upper genital tract, using nine hysterectomy and salpingo-oophorectomy specimens affected by HPV-positive invasive cervical carcinomas, to establish if cervical HPV infection can spread to upper tracts of the female genital system. HPV DNA was evaluated by polymerase chain reaction (PCR) in all cervical carcinomas as well as in all tracts of the genital system. Then, these data were compared with the results obtained from PCR study of five other hysterectomy and salpingo-oophorectomy specimens (control cases). The criteria used for selection of the control cases were informed consent of the patients for research at the time of surgery, absence of neoplasms, absence of any anatomic lesion caused by HPV in cervix, and external genitalia. All selected cases were squamous cervical carcinomas. PCR analysis revealed HPV DNA in all cases of cervical carcinoma. The HPV DNA was detected as weak positivity on PCR analysis in other organs of the genital system. However, the distribution of HPV DNA varied in the various cases and in the different tracts of the same hysterectomy and salpingo-oophorectomy specimen. We believe that the HPV DNA, detected as a weakly positive signal, in the upper genital tract of patients who have a cervical squamous carcinoma could be a reflection of a latent HPV infection, as well as a sign of the existence of micrometastases containing HPV DNA, which cannot be detected by conventional histologic techniques.


[EDA mutation screening and phenotype analysis in patients with tooth agenesis].
To screen the ectodysplasin A (EDA) gene mutation in the patients with non-syndromic tooth agenesis and ectodermal dysplasia, and to analyze the phenotype of missing teeth pattern in these two groups of patients. In the study, 174 patients with tooth agenesis (143: non-syndromic, 31: ectodermal dysplasia) and 451 health control volunteers were enrolled from the clinic, and the genome DNA was extracted from either peripheral blood or oral mucosal swab. The coding region of EDA gene was then amplified by PCR, sequenced and blasted to online NCBI database. The missing teeth were recorded for all patients, and the missing teeth from patients with EDA mutation were compared among the different dentition sites. 33 patients were identified with EDA mutation. In the non-syndromic patients, 13/143(9.09%) were identified with EDA mutation, while in patients with ectodermal dysplasia, 20/31(64.52%) were found with EDA mutation. Ten novel EDA mutations were identified (c.769G>C[p.G257R ],c.936C>G[p.I312M],c.223G>A[p.E75K], .1166C>T[p.P389L],c.133G>C[p.G45R],c.1109G>A[p.E370K],c.914G>T[p.S305I], c.916C>T[p.Q306X],c.602G>T[p.G201V],c.88-89insG[p.A30GfsX69]). For each dentition site there was no statistic difference in the number of missing teeth between the left and right sides, so the number from both sides were combined later in the analysis. In the patients with EDA mutation, the non-syndromic patients had fewer missing teeth (15.9±6.4 missing teeth for each, 207/364 in total) than the patients with ectodermal dysplasia (23.9±4.3, 478/560). In the non-syndromic patients with EDA mutation, the maxillay central incisors and first molars were less affected, with the same missing rate as 19.2% (5/26). While the mandibular central incisors (with a missing rate of 76.9%, 20/26), the maxillary lateral incisors (the missing rate: 88.5%, 23/26), the mandibular lateral incisors (the missing rate: 80.8%, 21/26), and the maxillary first premolars (the missing rate: 80.8%, 21/26) were more likely to be missing. In the ectodermal dysplasia patients with EDA mutation, only maxillary central incisors (the missing rate: 60%, 24/40), maxillary canines (the missing rate: 70%, 28/40), mandibular canines (the missing rate: 67.5%, 27/40), maxillary first molars (the missing rate: 65%, 26/40) and mandibular first molars (the missing rate: 72.5%, 29/40) had higher possibility of persistence. Teeth at other dentition sites were more likely to be affected (the minimum missing rate: 87.5%, 35/40). The findings would help to reveal the EDA gene and its function in ectodermal organogenesis.


Transmission of simian acquired immunodeficiency syndrome (SAIDS) with blood or filtered plasma.
Simian acquired immunodeficiency syndrome (SAIDS), a disease clinically and pathologically similar to acquired immunodeficiency syndrome in humans, was transmitted from diseased rhesus monkeys (Macaca mulatta) to normal monkeys by inoculation with heparinized whole blood or plasma that had been passed through filters of 0.45 micrometer pore size. This suggests that the causative agent is small and most probably a virus. No viruses, however, were isolated by standard cell culture techniques from the blood or filtered plasma which caused SAIDS. Both cellular and humoral immunity were markedly depressed in animals with advanced SAIDS.


African-American girls' dietary intake while watching television.
Television viewing has been associated with childhood obesity, although the mechanisms that link television viewing to higher BMI have not been established. Therefore, our objectives, in this report, were to describe the amount and types of foods that African-American girls consume while watching television and to examine the associations between African-American girls' BMI and the food they consume while watching television. Data were collected from 210 8- to 10-year-old African-American girls at four field centers by trained and certified nutritionists. Two nonconsecutive 24-hour dietary recalls were collected from each girl. For each eating episode reported, the girls were asked if they had been watching television while eating. Height and weight were collected using standard methods and used to calculate BMI. The data were analyzed separately by field center. The proportion of average daily energy intake that the girls consumed while watching television ranged from 26.9% to 35.0%. At all field centers, 40% to 50% of evening meals were consumed while watching television. None of the Spearman correlations between girls' BMI and the amount and type of foods consumed while watching television or at other times during the day were statistically significant (p > 0.05). This research revealed that a significant proportion of African-American girls' daily energy intake is consumed while watching television. Interventions that target reductions in food consumption while watching television or reducing television viewing may be effective strategies to decrease children's energy intakes. These results support a need for research to test the efficacy of these approaches.


Interactive e-learning courses in human genetics: usage and evaluation by science and medical students at the faculty of medicin.
This study presents our online-teaching material within the k-MED project (Knowledge in Medical Education) at the university of Marburg. It is currently organized in five e-learning modules: cytogenetics, chromosomal aberrations, formal genetics, fundamentals of molecular diagnostics, and congenital abnormalities and syndromes. These are basic courses intended to do the educational groundwork, which will enable academic teachers to concentrate on more sophisticated topics during their lectures. The e-learning modules have been offered to a large group of about 3300 students during four years at the Faculty of Medicine in Marburg. The group consists of science students (human biology) and medical students in the preclinical or the clinical period, respectively. Participants were surveyed on acceptance by evaluating user-tracking data and questionnaires. Analysis of the evaluation data proofs the broad acceptance of the e-learning modules during eight semesters. The courses are in stable or even increasing use from winter term 2005/06 until spring term 2009. Our e-learning-model is broadly accepted among students with different levels of knowledge at the Faculty of Medicine in Marburg. If the e-learning courses are maintained thoroughly, minor adaptations can increase acceptance and usage even furthermore. Their use should be extended to the medical education of technical assistances and nurses, who work in the field of human genetics.


Long-term treatment with a beta-blocker timolol attenuates renal-damage in diabetic rats via enhancing kidney antioxidant-defense system.
The factors with increasing diabetes-prevalence lead to significant global increases in chronic kidney disease. Since hyperglycemia generates more ROS and attenuates cellular antioxidant-defense mechanisms, numerous studies demonstrated that hyperglycemia-induced oxidative stress played a major role in the extracellular matrix expansion in tissues. Although no direct relation between activation of beta-adrenergic (β-AR) system and kidney disease in diabetes and since β-blockers demonstrate marked beneficial effects due to their scavenging free radicals and/or acting as an antioxidant in diabetic animal studies, the eventual objective of the present study was to determine whether timolol-treatment of streptozotocin-induced diabetic rats (5 mg/kg, daily following diabetes-induction, for 12-week) has advantage to prevent hyperglycemia-induced renal-damage via enhancing the depressed antioxidant defense in the kidney. Light microscopy data and their quantification demonstrated that timolol-treatment prevented basically glomerular hypertrophy, expansion in mesangium cell size, thickening and fibrosis in glomerular basement membrane, and accumulation of glycogen into tubular epithelial cells. Additionally, electron microscopy data demonstrated that timolol-treatment could also prevent diabetes-induced changes in the kidney tissue such as hypertrophy in podocytes, lost of filtration gaps and slit-diaphragms, and vacuolization in the distal tubular cells. Biochemical analysis basically on enzymes of antioxidant-defense system, including glutathione-S-transferase, glutathione reductase, and glucose-6-phosphate dehydrogenase, further supported that diabetes-induced damage in the kidney is mostly dependent on the increased oxidative stress and timolol, having an antioxidant-like action, could protect the kidney against hyperglycemia-induced damage without normalization of high-blood glucose level. Consequently, it can be suggested that although β-blockers are widely used for the treatment of cardiovascular diseases, β-blocker therapy of diabetics seems to be a new therapeutic approach against hyperglycemia-induced kidney damage in diabetic patients.


Microleakage evaluation around retrograde filling materials prepared using conventional and ultrasonic techniques.
The importance of the retrograde cavity preparation and the material used to restore is of utmost importance to achieve successful surgical endodontics. The aim of the present study is to evaluate the apical micro-leakage of root end cavities filled with Mineral trioxide aggregate, Biodentine and light cure GIC using two different cavity preparation techniques that is conventional bur preparation and ultrasonic tip preparation. Eighty extracted single rooted human teeth (except mandibular incisors) with one canal, fully developed apices and without any major carious lesion are collected for the study. The teeth were sectioned at CEJ to standardize the length. Roots are instrumented upto master apical file 40 K size and obturated with gutta percha and AH plus sealer in lateral condensation technique. The teeth were then resected apically at 90° angle axis to the long axis of the root removing 3 mm of the apex. The teeth were divided in to four groups of 20 each- • Group I- samples restored with MTA. • Group II- samples restored with Biodentine. • Group III- (Positive control group)- samples restored with Light activated GIC. • Group IV - (negative control group)- no filling material. Each group is divided into two subgroups (a, b) of ten teeth each 1. Retropreparation done with ultrasonic retrotip. 2. Retropreparation done with conventional bur. The teeth were then immersed in 0.5% Rhodamine B dye for 48 h. The teeth were split longitudinally and the interface between the restored material and the canal wall is observed under Confocal laser scanning microscope. Depth of dye penetration was examined under stereomicroscope. The statistical analysis was performed by One way ANOVA, t test. Pair wise comparision was done by Newman - Keuls multiple post hoc test. The mean values of Dye penetration for Group Ia (321.23), Group Ib (490.11), Group IIa (1065.14), Group IIb (1170.96), Group IIIa (1888.90), Group IIIb (2025.35). The samples prepared with ultrasonic retrotip showed less microleakage but it is statistically not significant. MTA showed significantly less microleakage when compared to Biodentine and light cure GIC and there is no statistical difference between the ultrasonic retrotip preparation and conventional bur preparation.


Respiratory cancers and pollution.
Cancer is the major public health problem worldwide, irrespective of the socio-economic status of the countries. Even though the overall mortality from cancer is higher in the western countries, the cancer burden is on the rise in under-developed countries, with a projected 81-100% increase by 2030, mostly due to pollution and tobacco use. Respiratory cancers affect the lung, larynx, trachea, and bronchus and depending on the location of the cancer, the symptoms change and also the risks, incidence and survival outcomes differ accordingly. Besides tobacco use, chronic exposure to household pollution is known to be associated with elevated risk of lung cancer and other cancers. Women and children living in severe poverty in the underdeveloped countries are exposed most to household air pollution and, thus, suffer its consequences maximally, and household air pollution, specifically arising from solid fuel burning, which accounts for nearly 4 million deaths throughout the world annually. Cancers affecting the respiratory tract, including both nasopharyngeal cancer and lung cancer, are strongly associated with pollution from coal and other solid fuel burning. Lung cancer, which is of two types, small cell lung carcinoma and the non-small cell lung cancer, is the most common and fatal cancer. Even though tobacco has been viewed as the major risk for respiratory cancers, it is now evident that household pollution, exposure to asbestos, chromium and arsenic etc, all pose a significant risk for respiratory cancers. Preventive steps to curtail the many sources of air pollution by improving living conditions and reducing the occupational exposure hazards like welding, industrial work etc., are markedly needed to control the incidence of respiratory cancers.


Developing a theory-based instrument to assess the impact of continuing professional development activities on clinical practice: a study protocol.
Continuing professional development (CPD) is one of the principal means by which health professionals (i.e. primary care physicians and specialists) maintain, improve, and broaden the knowledge and skills required for optimal patient care and safety. However, the lack of a widely accepted instrument to assess the impact of CPD activities on clinical practice thwarts researchers' comparisons of the effectiveness of CPD activities. Using an integrated model for the study of healthcare professionals' behaviour, our objective is to develop a theory-based, valid, reliable global instrument to assess the impact of accredited CPD activities on clinical practice. Phase 1: We will analyze the instruments identified in a systematic review of factors influencing health professionals' behaviours using criteria that reflect the literature on measurement development and CPD decision makers' priorities. The outcome of this phase will be an inventory of instruments based on social cognitive theories. Phase 2: Working from this inventory, the most relevant instruments and their related items for assessing the concepts listed in the integrated model will be selected. Through an e-Delphi process, we will verify whether these instruments are acceptable, what aspects need revision, and whether important items are missing and should be added. The outcome of this phase will be a new global instrument integrating the most relevant tools to fit our integrated model of healthcare professionals' behaviour. Phase 3: Two data collections are planned: (1) a test-retest of the new instrument, including item analysis, to assess its reliability and (2) a study using the instrument before and after CPD activities with a randomly selected control group to explore the instrument's mere-measurement effect. Phase 4: We will conduct individual interviews and focus groups with key stakeholders to identify anticipated barriers and enablers for implementing the new instrument in CPD practice. Phase 5: Drawing on the results from the previous phases, we will use consensus-building methods to develop with the decision makers a plan to implement the new instrument. This project proposes to give stakeholders a theory-based global instrument to validly and reliably measure the impacts of CPD activities on clinical practice, thus laying the groundwork for more targeted and effective knowledge-translation interventions in the future.


Solubility of inert gases in biological fluids and tissues: a review.
Data have been tabulated from more than 150 references on the solubility of inert gases in fluids and tissues of biological interest. Thirty-two gases have been studied in blood with measured solubility ranging from 0.005 to 16 ml of gas at 37 degrees C per ml of blood per ATA (Ostwald coefficient). For most gases, solubility in other tissues such as muscle or brain is between 60% and 300% of blood solubility. Measured solubilities in biological tissues do not correspond well to solubility in water and oil. Most gases decrease in solubility by 1%-6% for each degree C rise in temperature. The effect of pressure on solubility has not been well studied, and only crude estimates can be obtained by using methods of chemical thermodynamics.


Acute aortic thrombosis and antithrombin III deficiency in the nephrotic syndrome: a case report.
A 25-year-old Oriental woman with nephrotic syndrome was admitted to the United States Naval Hospital in Okinawa. She had acute aortic thrombosis, which was managed initially with bilateral femoral thrombectomy and calf fasciotomies. In the early postoperative period, increasing doses of heparin were required to maintain adequate anticoagulation. Hematologic evaluation revealed a deficiency of antithrombin III (AT-III). Such a deficiency has been recognized as occurring in nephrotic syndrome, most probably due to urinary loss of this serum protein. Five prior cases of acute aortic thrombosis have been described in the nephrotic syndrome, but only three reports of acute aortic thrombosis have been attributed to documented AT-III deficiency. Acute thrombosis due to AT-III deficiency may be confirmed by measuring decreased serum levels of this protein. Treatment is initiated with fresh frozen plasma and heparin, with subsequent utilization of oral warfarin.


Health care and the global community.
Catholic health systems and facilities, to fulfill their commitment to the healing ministry of Jesus Christ, are called to serve society's most poor and vulnerable people. This calling applies to people in need not only locally but also internationally. Individuals and organizations providing aid in foreign lands will face many challenges. Yet if they believe that they can use their expertise to benefit people in need, they can accomplish their goals. Some guiding principles are instructive for those undertaking international outreach efforts: Partners must commit themselves to a common mission; the effort must focus on empowering aid recipients; participants in the effort-donors and recipients alike-can experience transformation; and health and well-being must be central to the work. The Catholic Consortium for International Health Services (CCIHS) has experience in following these principles to bring about change. The consortium can help ministry organizations achieve their international outreach goals.


Prevalence of and factors associated with extraintestinal manifestations and their remission in inflammatory bowel disease: the EXTRA prospective study from the GETAID.
Extraintestinal manifestations (EIM) of inflammatory bowel disease (IBD) are challenging clinical situation. No prospective study assessed remission risk factors for EIMs. Study aimed to prospectively investigate the epidemiology, risk factors for EIM occurrence and EIM remission in a large IBD cohort. We conducted a cross-sectional study in 30 French referral centers. Between May to June 2021, all consecutive patients attending to hospital appointment were systematically invited to fill out a questionnaire. A total of 1971 consecutive patients with IBD were analyzed. There were 1056 women (53.8%), and the median age of patients was 41 years [31; 54]. The median disease duration was 11 years [1; 18]. Overall, 544 (27.6%) had at least one EIM. In 20.2% of case, patient had multiple EIMs. The most frequent EIMs were rheumatological (19%) and dermatological (10%) manifestations. Immunosuppressant treatment (OR=2.56; p<0.001) was a risk factor for EIM, while the Montreal A3 classification (OR=0.61, p=0.023) and male gender (OR=0.61, p<0.001) were associated with a lower risk for EIM occurrence. IBD current clinical remission (OR=2.42; p<0.001) and smoking cessation (OR=2.98; p<0.001) were associated factors for EIM remission. Conversely, age at IBD diagnosis (OR=0.98; p<0.018) was associated with a lower risk of EIM remission. One quarter of patients had at least one EIM. Beyond factors associated with the presence of EIMs, patients with IBD current clinical remission and smoking cessation are more likely to achieve EIM remission, while increasing age at IBD diagnosis is associated with decreased chance of remission.


Venous thromboembolism: diagnosis and management of deep venous thrombosis.
Venous thromboembolism (VTE) affects 1-2 per 1000 people in the general population each year. Clinical diagnosis of deep venous thrombosis (DVT) is unreliable, and must be confirmed by compression ultrasonography or venography. A low clinical pretest probability of DVT and negative D-dimer result reliably exclude the diagnosis, with no need for diagnostic imaging. Initial treatment of DVT is with low-molecular-weight heparin or unfractionated heparin for at least 5 days, followed by warfarin (target INR, 2.0-3.0) for at least 3 months. A vena cava filter is indicated in patients who are ineligible for anticoagulant therapy or who experience embolism despite therapeutic anticoagulation. Thrombolysis or surgical embolectomy may be used as a limb-saving measure in patients with extensive proximal DVT and circulatory compromise that threatens the viability of the leg. Decisions regarding the optimal duration of anticoagulation to prevent recurrent VTE should be individualised and balance the risk of recurrence if warfarin is stopped against the risk of major bleeding and inconvenience of continuing treatment. The risk of recurrence is highest in people with recurrent unprovoked DVT or chronic predisposing factors (eg, cancer) who require indefinite anticoagulant treatment.


Major depression and dysthymia in children and adolescents: discriminant validity and differential consequences in a community sample.
To evaluate evidence, in a community sample, for discriminant validity between major depression (MDD) and dysthymia (Dy) in children and adolescents and to examine differential consequences of the 2 disorders for functioning. The National Institute of Mental Health (NIMH) Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) study consists of probability samples of youths. Data for this study are derived from interviews with 1,285 complete parent-youth pairs aged 9 to 17 years from 4 geographic areas in the United States. Youths with MDD were contrasted with those with Dy and those with both (MDD-Dy) on the NIMH Diagnostic Interview Schedule for Children, Non-Clinician Children's Global Assessment Scale, Columbia Impairment Scale, and the Service Utilization and Risk Factors Module. Groups with MDD, Dy, or MDD-Dy did not differ on sociodemographic, clinical, or family and life event variables. Youths with combined MDD-Dy were significantly less competent and more impaired than youths with either disorder alone. The findings do not provide support for the differentiation of MDD and Dy but strongly suggest the importance of addressing the needs of youths who meet criteria for both MDD and Dy because this combination is likely to be both serious and disruptive of normal developmental processes.


Impact of the Persistence of Three Essential Oils with Antifungal Activities on Stored Wheat Grains, Flour, and Baked Products.
Wheat grains are exposed to several plagues after harvesting and during storage. These plagues include bacteria, fungi, and insects with detrimental outcomes to their quality and heavy losses to the farmers. Fungi are of special interest because of their ability to produce mycotoxins with health concerns. Once grains are harvested, synthetic fungicides, which are sprayed before long-term storage, normally control fungi; however, these synthetic products represent a health concern because of their toxicities. Previously, we reported the antifungal activity of the essential oils extracted from Porophyllum linaria, Agastache mexicana, and Buddleja perfoliata against fungal strains isolated from stored wheat. In this study, we sprayed wheat grains with the same essential oils to measure their persistence interval and to prepare baked products to assess potential changes in their physical properties. The persistence interval of the essential oils in grains indicated that it takes between 63 and 134 days to eliminate 90% of the original compounds. This extended time of the compounds in the grains together with a lack of physical properties modifications of the flour and baked products (post-treatment) suggest that the presence of oils in the grains is potentially safe to use. The solid data denote the technological feasibility of the treatment and the possible management of residues through adequate safety intervals.


Comparison between First- and Second-Generation Cryoballoon for Paroxysmal Atrial Fibrillation Ablation.
Introduction. Cryoballoon (CB) ablation has emerged as a novel treatment for pulmonary vein isolation (PVI) for patients with paroxysmal atrial fibrillation (PAF). The second-generation Arctic Front Advance (ADV) was redesigned with technical modifications aiming at procedural and outcome improvements. We aimed to compare the efficacy of the two different technologies over a long-term follow-up. Methods. A total of 120 patients with PAF were enrolled. Sixty patients underwent PVI using the first-generation CB and 60 patients with the ADV catheter. All patients were evaluated over a follow-up period of 2 years. Results. There were no significant differences between the two groups of patients. Procedures performed with the first-generation CB showed longer fluoroscopy time (36.3 ± 16.8 versus 14.2 ± 13.5 min, resp.; p = 0.00016) and longer procedure times as well (153.1 ± 32 versus 102 ± 24.8 min, resp.; p = 0.019). The overall long-term success was significantly different between the two groups (68.3 versus 86.7%, resp.; p = 0.017). No differences were found in the lesion areas of left and right PV between the two groups (resp., p = 0.61 and 0.57). There were no significant differences in procedural-related complications. Conclusion. The ADV catheter compared to the first-generation balloon allows obtaining a significantly higher success rate after a single PVI procedure during the long-term follow-up. Fluoroscopy and procedural times were significantly shortened using the ADV catheter.


Mechanism-Based Rational Discovery and In Vitro Evaluation of Novel Microtubule Stabilizing Agents with Non-Taxol-Competitive Activity.
Microtubules (MT) are cytoskeletal polymers of αβ-tubulin dimers that play a critical role in many cellular functions. Diverse antimitotic drugs bind to MT and disrupt their dynamics acting as MT stabilizing or destabilizing agents. The occurrence of undesired side effects and drug resistance encourages the search for novel MT binding agents with chemically diverse structures and different interaction profiles compared to known active compounds. This work reports the rational discovery of seven novel MT stabilizers using a combination of molecular modeling methods and in vitro experimental assays. Virtual screening, similarity filtering, and molecular mechanics generalized Born surface area (MM/GBSA) binding free energy refinement were employed to select seven potential candidates with high predicted affinity toward the non-taxoid site for MT stabilizers on β-tubulin. MD simulations of 150 ns on reduced MT models suggest that candidate compounds strengthen the longitudinal interactions between tubulin dimers across protofilaments, which is a primary molecular mechanism of action for known MT stabilizers. In vitro MT polymerization assays confirmed that all candidates promote MT assembly at concentrations of >50 mM and exhibit noncompetitive MT polymerization profiles when cotreating with Taxol. Preliminary HeLa cell viability assays revealed a moderate cytotoxic effect for the compounds under study at 100 μM concentration. These results support the validity of our rational discovery strategy and the use of molecular modeling methods to pursue the search and optimization of new MT targeting agents.


Voluntary long-term care insurance: best practices for increasing employee participation.
This is the second of two Issue Briefs (April and May 2000) on long-term care (LTC) insurance. The previous Issue Brief addressed the problem of increasing sponsorship, while this report addresses the issue of increasing employee participation. Participation rates in group LTC insurance plans tend to be low. A potential watershed event for the development of the employment-based group LTC market is the proposed LTC program for federal employees and retirees (a program that would have to be enacted by Congress). The perception of a successful offering to federal employees could provide an enormous boost to the group LTC insurance market. Employee communication and education are seen as critical to the success of LTC enrollments. The importance of support shown by an employer for a new LTC plan offering cannot be overstated. Unlike 401(k) plan participation trends, LTC participation rates are highest among large companies. Insurers tend to view the 40-60 age range as the primary target for group LTC insurance, and employee salary as the best predictor of LTC insurance enrollment. Higher educational levels also are associated with higher levels of LTC participation. Perceived need for LTC insurance is perhaps the biggest barrier to the purchase of LTC insurance by employees due to competing financial priorities and the fact that LTC issues are generally off the "radar screens" of younger employees. Plans with skilled nursing home and home care benefits experience higher participation rates than plans lacking these benefits. The availability of lower-cost and long duration benefit options can be an important factor in determining participation. Most sponsors have chosen to offer noncontributory (i.e., fully employee-paid) LTC plans. Employer reluctance to make contributions may be caused by HIPAA's prohibition on the inclusion of LTC insurance in cafeteria plans. One of the major advantages of group LTC plans is the availability of guaranteed issue (i.e., issuing coverage without requiring evidence of insurability) for employees, which is not available in the individual LTC market. It is easy for enrollment to be derailed by the presence of any of a number of harmful conditions, such as employer-sponsors who distance themselves from the offer, ineffective communications, or difficult enrollment processes. Achieving consistently strong levels of participation in LTC plans will require employer-sponsors and their insurance carriers to form strong partnerships, with worker participation as their primary stated goal.


Occupational therapy synergy between Comprehensive Community Based Rehabilitation Tanzania and Heifer International to reduce poverty.
This article describes a partnership between a community-based rehabilitation organisation and a non-governmental organisation (NGO) in Tanzania. The partnership focused on income-generating (IG) activities to tackle the problems of poverty faced by families with a child with a disability (CWD). The aim of this case study was to describe the partnership between Comprehensive Community Based Rehabilitation Tanzania in Moshi (CCBRT-Moshi), a non-governmental organisation, and families to create an income-generating business, namely raising goats. This was a team approach between CCBRT-Moshi and Heifer International, an organisation that focuses on IG activities to create a synergy or partnership between community-based rehabilitation and IG activities. This partnership between occupational therapy rehabilitation services at CCBRT-Moshi and the NGO resulted in strengthening the effectiveness of occupational therapy services and leaving a more lasting impact on the people they served within the community by helping to reduce poverty in addition to providing rehabilitation and prevention interventions. This collaboration was successful as it provided a means for families to generate income from raising goats. Although the results have not been empirically verified, observational and anecdotal evidence suggests that families with CWDs have better quality of life and ultimately improved health through this synergistic partnership.


Translocation of ATP into the lumen of rough endoplasmic reticulum-derived vesicles and its binding to luminal proteins including BiP (GRP 78) and GRP 94.
Rat liver and canine pancreas rough endoplasmic reticulum-derived vesicles, which were sealed and of the same topographical orientation as in vivo, were used in a system in vitro to demonstrate translocation of ATP into their lumen. Translocation of ATP is saturable (apparent Km: 3-4 microM and Vmax: 3-7 pmol/min/mg of protein) and protein mediated because treatment of intact vesicles with Pronase, N-ethylmaleimide, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid inhibit transport. The entire ATP molecule is being translocated; this was shown by high performance liquid chromatography analysis and the use of a nonhydrolyzable analog. Control experiments rule out that translocation of ATP attributed to rough endoplasmic reticulum-derived vesicles is due to contamination by mitochondria and Golgi vesicles. Following translocation of ATP into the lumen of the vesicles, binding to luminal proteins including BiP (immunoglobulin heavy chain-binding protein-glucose-regulated protein 78) and glucose-regulated protein 94 was observed. This binding appeared to be specific because similar experiments with GTP were negative. These studies strongly suggest that translocation of ATP into the rough endoplasmic reticulum lumen may serve as a mechanism for making ATP available in proposed energy requiring reactions within the lumen.


Validation of a Natural Language Machine Learning Model for Safety Literature Surveillance.
As part of routine safety surveillance, thousands of articles of potential interest are manually triaged for review by safety surveillance teams. This manual triage task is an interesting candidate for automation based on the abundance of process data available for training, the performance of natural language processing algorithms for this type of cognitive task, and the small number of safety signals that originate from literature review, resulting in its lower risk profile. However, deep learning algorithms introduce unique risks and the validation of such models for use in Good Pharmacovigilance Practice remains an open question. Qualifying an automated, deep learning approach to literature surveillance for use at AstraZeneca. The study is a prospective validation of a literature surveillance triage model, comparing its real-world performance with that of human surveillance teams working in parallel. The biggest risk in modifying this triage process is missing a safety signal (resulting in model false negatives) and hence model recall is the main evaluation metric considered. The model demonstrates consistent global performance from training through testing, with recall rates comparable to that of existing surveillance teams. The model is accepted for use specifically for those products where non-inferiority to the manual process is rigorously demonstrated. Characterizing model performance prospectively, under real-world conditions, allows us to thoroughly examine model consistency and failure modes, qualifying it for use in our surveillance processes. We also identify potential future improvements and recognize the opportunity for the community to collaborate on this shared task.


Self-reported functioning and well-being in patients with Parkinson's disease: comparison of the short-form health survey (SF-36) and the Parkinson's Disease Questionnaire (PDQ-39)
The purpose of this paper was to document the impact of Parkinson's disease (PD) upon patients using both a generic health status measure (the Short-form 36 health survey questionnaire, SF-36) and a disease-specific measure (the 39-item Parkinson's Disease Questionnaire, PDQ-39). Comparing the results of the SF-36 in this population with a similar aged group selected randomly from two general practices it was evident that the disease has considerable impact on general levels of functioning and well-being. Furthermore, other areas not contained on the SF-36 were found to be relevant to PD patients. It is suggested that the disease-specific measure will be of value, ideally alongside a generic measure, in studies aimed at determining the impact of a treatment régimen upon PD patients, or to monitor the long-term progress of cohorts of patients with PD. The paper highlights the need for careful consideration of measures for evaluation.


Pharmacological profile of sulodexide.
Since its introduction, sulodexide has been used on and off for several indications. More recently this agent has become revitalized and tested in newer indications. Sulodexide is composed of glycosaminoglycan that includes a mixture of fast-moving heparin and dermatan sulfate. It exerts its anticoagulant and antithrombotic action through interactions with both AT and HCII. Sulodexide has been proven to have effects on the fibrinolytic system, platelets, endothelial cells, inflammation and more recently metalloproteases. The administration of sulodexide results in the release of lipoprotein lipase and has been shown to reduce the circulating level of lipids. It has also shown to decrease the viscosity of both whole blood and plasma. Sulodexide differs from heparin in its oral bioavailability and longer half-life. There is also less bleeding associated with sulodexide. In addition, oral administration of sulodexide does not interfere with the pharmacologic actions of commonly used agents. Similar to heparin, sulodexide releases TFPI which contributes to its antithrombotic effect and anti-inflammatory properties. Sulodexide has been proven to be effective in peripheral arterial thrombosis and venous thrombosis. It is also clinically active in the treatment of venous leg ulcers and intermittent claudication. More recent data suggest that sulodexide can be used in tinnitus and in vascular vertigo. Additional studies in these indications are required. Sulodexide was generally safe and well tolerated in the clinical trials, without any severe bleeding complications. Therefore sulodexide appears to be a good treatment for all arterial and venous diseases and for the prevention of progression of disease.


Safety and Efficacy of Limited Laboratory Monitoring for Hepatitis C Treatment: A Blinded Clinical Trial in Rwanda.
Direct-acting antivirals for hepatitis C virus (HCV) are highly effective and well-tolerated. However, only a small percentage of HCV-infected individuals globally have received therapy. Reducing the complexity of monitoring during HCV therapy, if shown to be safe, could facilitate greater access to HCV services, particularly in resource-limited settings such as sub-Saharan Africa. We enrolled a total of 300 patients who were chronically infected with genotype 4 HCV in Rwanda and treated them with fixed-dose ledispasvir/sofosbuvir for 12 weeks. For 60 consecutive participants enrolled, we blinded the study clinician to on-treatment laboratory results. We compared the efficacy, safety, and tolerability in those with blinded laboratory results to those with standard laboratory monitoring. Baseline characteristics among those with blinded laboratory values were comparable to those with standard monitoring. Among both groups, the median age was 63 years, and the median HCV viral load was 5.9 log (versus 64 years and 6.0 log, respectively). Sustained virologic response rates at 12 weeks after treatment completion were similar in those with blinded laboratories (87%) compared to those with standard laboratory monitoring (87%). There was no increase in adverse events in those with blinded laboratory results, and no participants discontinued the study medication because of an adverse event. Conclusion: On-treatment laboratory monitoring did not improve patient outcomes in those treated with ledispasvir/sofosbuvir. Eliminating this monitoring in treatment programs in resource-limited settings may facilitate and accelerate scale-up of HCV therapy.


Microarray-based survey of CpG islands identifies concurrent hyper- and hypomethylation patterns in tissues derived from patients with breast cancer.
Maintenance of CpG island methylation in the genome is crucial for cellular homeostasis and this balance is disrupted in cancer. Our rationale was to compare the methylation of CpG islands in tissues (tumor, healthy breast and blood) from patients with breast cancer. We studied 72 genes in 103 samples using microarray hybridization and bisulfite sequencing. We observed tumor specific hyper- or hypomethylation of five genes; COL9A1, MT1A, MT1J, HOXA5 and FLJ45983. A general drop of methylation in COL9A1 was apparent in tumors, when compared with blood and healthy breast tissue. Furthermore, one tumor displayed a complete loss of methylation of all five genes, suggesting overall impairment of methylation. The downstream, evolutionary conserved island of HOXA5 showed hypomethylation in 18 tumors and complete methylation in others. This CpG island also displayed a semimethylated state in the majority of normal breast samples, when compared to complete methylation in blood. Distinct methylation patterns were further seen in MT1J and MT1A, belonging to the metallothionein gene family. The CpG islands of these genes are spaced by 2 kb, which shows selective methylation of two structurally and functionally related genes. The promoters of FLJ45983 and MT1A were methylated above 25% in 18 primary and metastatic tumors. Concurrently, there was also >10% methylation of healthy breast tissue in 11 and 5 samples, respectively. This suggests that the methylation process for the latter two genes takes place already in normal breast cells. Our results also point to a considerable heterogeneity of epigenetic disturbance in breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.


Faecal Campylobacter shedding among dogs in animal shelters across Texas.
Epidemiologic studies on faecal Campylobacter shedding among dogs in the United States have been limited, despite evidence that the incidence of human campylobacteriosis has increased over the last decade. Our objectives were to estimate the prevalence of faecal Campylobacter shedding among shelter dogs in Texas, to estimate the specific prevalence of Campylobacter jejuni and Campylobacter coli shedding, and to identify risk factors for Campylobacter-positive status. Using a cross-sectional study design, we collected faecal samples from dogs in six animal shelters across Texas between May and December, 2014. Quantitative PCR protocols were used to detect Campylobacter in samples and to specifically identify C. jejuni and C. coli. The prevalence of faecal Campylobacter shedding among sampled dogs was 75.7% (140/185). Prevalence varied significantly by shelter (p = .03), ranging from 57% to 93%. There was a marginal association (p = .06) between abnormal faecal consistency and positive Campylobacter status, after controlling for shelter as a random effect. However, approximately 70% of Campylobacter-positive dogs had grossly normal faeces. Campylobacter prevalence did not vary significantly by age group or sex. The prevalence of C. jejuni-positive samples was 5.4% (10/185), but C. coli was not detected in any samples. Dogs are a potential source of zoonotic Campylobacter transmission.


Nitrate removal in riparian wetlands: interactions between surface flow and soils.
Riparian wetlands containing springs are thought to be ineffective at removing nitrate because contact times between the upwelled ground water and the underlying microbially active soils are short. Tracer experiments using lithium bromide (LiBr) and nitrate (NO3-N) injected at the surface were used to quantify residence times and NO3-N removal in a riparian swale characteristic of New Zealand hill-country pasture. An experimental enclosure was used with collecting trays at the downstream end to measure flow and concentration, shallow wells to measure subsurface concentrations, and an array of logging conductivity probes to monitor tracer continuously. The majority of added tracer reached the outlet more slowly than could be explained by surface flow, but more quickly than could be explained by Darcy seepage flow. There was evidence from the wells of tracer diffusing vertically to a depth of at least 5 cm into the surface soil layer, which was permanently saturated and highly porous. During dry weather 24 +/- 9% of added NO3-N was removed over a distance of 1.5 m largely by denitrification. The net uptake length coefficient for this wetland (K = 0.08 +/- 0.03 m(-1)) is slightly higher than the range (K = 0.01-0.07 m(-1)) measured in a small stream channel infested with macrophytes. Nitrate removal is expected to decrease with increasing flow. Seepage flow is estimated to have removed only 7 +/- 4% of the added NO3-N and we hypothesize that vertical diffusion substantially increases NO3-N removal in this type of wetland. Riparian wetlands with springs and surface flows should not be dismissed as having low NO3-N removal potential without checking whether there is significant vertical mixing.


The complete nucleotide sequence of pea seed-borne mosaic virus RNA.
The complete nucleotide sequence of the RNA genome of pea seed-borne mosaic virus (PSbMV) was determined from cloned cDNA and by direct sequencing of viral RNA. The PSbMV genomic sequence was determined to be 9924 nucleotides in length excluding the poly(A) tract. The RNA contained an open reading frame (ORF) of 9618 nucleotides with the potential to encode a polyprotein with a calculated Mr of 364000 (364K). The ORF was flanked by a 5' untranslated leader sequence of 143 nucleotides and a 3' untranslated region of 163 nucleotides. A comparison of the PSbMV polyprotein with the polyproteins of the potyviruses tobacco etch virus (TEV), tobacco vein mottling virus (TVMV), plum pox virus (PPV) and potato virus Y (PVY) showed that PSbMV had a similar genome organization. The polyproteins had a high level of amino acid identity except in the N-terminal region, which varied in both sequence and length. Putative proteolytic cleavage sites were identified in the polyprotein of PSbMV by comparison with those identified for other potyviruses. The cleavage site between the 6K protein and the 49K proteinase is proposed to occur at the C-terminal side of glutamic acid and not at the C-terminal side of glutamine as in other potyviruses. In addition to the five proteolytic cleavage sites for the 49K proteinase identified previously, a sixth putative cleavage site was identified internally in the 49K proteinase of PSbMV, as well as in the 49K proteinases of TEV, TVMV, PPV, PVY and soybean mosaic virus. Cleavage at this site in the 49K proteinases of TEV, TVMV and PPV would result in an N-terminal protein of 22K to 24K, which is similar in size to the size determined for their VPgs.


Study on the Socio-Economic Impact of Cancer Disease on Cancer Patients and Their Relatives.
Cancer is one of the most relevant social and health problems in the world. The disease entails additional costs for cancer patients and their families that are not covered by the public part of our welfare state, and which they assume themselves simply because they are ill. The main objective of this study is to identify and analyse the additional cost and socioeconomic impact of cancer disease on patients diagnosed with cancer disease and their families. Descriptive cross-sectional randomised observational epidemiological study without replacement with prevalence of cancer disease in the study base, carried out in the Medical Oncology Service of the Complejo Asistencial Universitario de Salamanca (CAUSA), Spain. The study variable has been the additional cost of the cancer disease for cancer patients and their families that is not covered by our autonomous health system. Cancer disease entails an additional cost for the patient and family; more specifically, for 55% of the patients in the study sample, the diagnosis of cancer represents extra expenditure of between 8.38-9.67% of their annual income. Furthermore, the disability and dependence of patients does not represent an additional cost due to their levels of functionality, but it can have repercussions on the future cost of the evolution of the disease, in addition to the fact of having cancer.


CAD/CAM-Assisted Auricular Prosthesis Fabrication for a Quick, Precise, and More Retentive Outcome: A Clinical Report.
Auricular defects comprise a large proportion of maxillofacial deformities. Most patients with acquired deformities have psychosocial ineptness and seek cosmetic rehabilitation. Although minor defects can be corrected surgically, extensive deformities are difficult to reconstruct with plastic surgery. Contrary to that, prosthetic restoration can provide excellent esthetic results. The conventional methods of maxillofacial prosthesis fabrication are time consuming and the outcome depends on the technician's skill. The advent of CAD/CAM technology in the field of dentistry has brought enormous improvement in the quality of health care provided. In the past decade, several methods have been described employing CAD/CAM techniques for the cosmetic rehabilitation of auricular defects. This clinical report details the integration of multiple digital technologies of CT scanning, computer aided design, and rapid prototyping to construct an ear prosthesis with limited number of appointments.


A Prospective Randomized Study of Endoscopic Versus Conventional Harvesting of the Radial Artery.
The aims of the study were to determine whether endoscopic harvesting of the radial artery (RA) reduces morbidity due to pain, infection, and disability with improvement in satisfaction and cosmesis compared to the conventional technique and (2) to compare the 6-month angiographic patency of the RA harvested conventionally and endoscopically. In a prospective randomized study, 119 patients undergoing coronary artery bypass grafting using the RA were randomized to have RA harvested either conventionally (n = 59) or endoscopically (n = 60). Radial artery harvest time (open wound time) was significantly reduced in the endoscopic group (36.5 ± 9.4 vs 57.7 ± 9.4 minutes, P < 0.001). Only one patient developed wound infection (1.6%) in the endoscopic group compared with six patients (10.2%), P = 0.061, in the conventional group. Although this was not statistically significant, clinically this was relevant in terms of reduction in postoperative morbidity. Postoperative pain in the arm incision was significantly lower in the endoscopic group at postoperative day 2 (P < 0.001) and at discharge (P < 0.001) and similar to the conventional open group at 6 weeks' follow-up (P = 0.103). Overall patient satisfaction and cosmesis were significantly better in the endoscopic group at postoperative day 2 (P < 0.001), at discharge (P < 0.001), and at 6 weeks' follow-up (P < 0.001). There was no difference in the arm disability postoperatively (P = 0.505) between the two groups. Six-month angiographic assessment of 23 patients (12 endoscopic and 11 open) revealed no difference in the patency rate (10/12 in endoscopic and 9/11 in open group). Endoscopic RA harvesting reduced the incidence of postoperative wound infection and wound pain and improved patient satisfaction and cosmesis compared with conventional harvesting technique. There was no difference in the 6-month angiographic patency of the RA harvested conventionally and endoscopically.