AntiBP2: improved version of antibacterial peptide prediction.
Antibacterial peptides are one of the effecter molecules of innate immune system. Over the last few decades several antibacterial peptides have successfully approved as drug by FDA, which has prompted an interest in these antibacterial peptides. In our recent study we analyzed 999 antibacterial peptides, which were collected from Antibacterial Peptide Database (APD). We have also developed methods to predict and classify these antibacterial peptides using Support Vector Machine (SVM). During analysis we observed that certain residues are preferred over other in antibacterial peptide, particularly at the N and C terminus. These observation and increased data of antibacterial peptide in APD encouraged us to again develop a new and more robust method for predicting antibacterial peptides in protein from their amino acid sequence or given peptide have antibacterial properties or not. First, the binary patterns of the 15 N terminus residues were used for predicting antibacterial peptide using SVM and achieved accuracy of 85.46% with 0.705 Mathew's Correlation Coefficient (MCC). Then we used the binary pattern of 15 C terminus residues and achieved accuracy of 85.05% with 0.701 MCC, latter on we developed prediction method by combining N & C terminus and achieved an accuracy of 91.64% with 0.831 MCC. Finally we developed SVM based model using amino acid composition of whole peptide and achieved 92.14% accuracy with MCC 0.843. In this study we used five-fold cross validation technique to develop all these models and tested the performance of these models on an independent dataset. We further classify antibacterial peptides according to their sources and achieved an overall accuracy of 98.95%. We further classify antibacterial peptides in their respective family and got a satisfactory result. Among antibacterial peptides, there is preference for certain residues at N and C terminus, which helps to discriminate them from non-antibacterial peptides. Amino acid composition of antibacterial peptides helps to demarcate them from non-antibacterial peptide and their further classification in source and family. Antibp2 will be helpful in discovering efficacious antibacterial peptide, which we hope will be helpful against antibiotics resistant bacteria. We also developed user friendly web server for the biological community.


Breast cancer detection using neutron stimulated emission computed tomography: prominent elements and dose requirements.
Neutron stimulated emission computed tomography (NSECT) is being developed to noninvasively determine concentrations of trace elements in biological tissue. Studies have shown prominent differences in the trace element concentration of normal and malignant breast tissue. NSECT has the potential to detect these differences and diagnose malignancy with high accuracy with dose comparable to that of a single mammogram. In this study, NSECT imaging was simulated for normal and malignant human breast tissue samples to determine the significance of individual elements in determining malignancy. The normal and malignant models were designed with different elemental compositions, and each was scanned spectroscopically using a simulated 2.5 MeV neutron beam. The number of incident neutrons was varied from 0.5 million to 10 million neutrons. The resulting gamma spectra were evaluated through receiver operating characteristic (ROC) analysis to determine which trace elements were prominent enough to be considered markers for breast cancer detection. Four elemental isotopes (133Cs, 81Br, 79Br, and 87Rb) at five energy levels were shown to be promising features for breast cancer detection with an area under the ROC curve (A(Z)) above 0.85. One of these elements--87Rb at 1338 keV--achieved perfect classification at 10 million incident neutrons and could be detected with as low as 3 million incident neutrons. Patient dose was calculated for each gamma spectrum obtained and was found to range from between 0.05 and 0.112 mSv depending on the number of neutrons. This simulation demonstrates that NSECT has the potential to noninvasively detect breast cancer through five prominent trace element energy levels, at dose levels comparable to other breast cancer screening techniques.


Novel Multifunctional Nanoagent for Visual Chemo/Photothermal Therapy of Metastatic Lymph Nodes via Lymphatic Delivery.
Breast cancer is one of the major diseases that threaten women's health. Lymph node (LN) metastasis is the most common metastatic path of breast cancer. Finding a simple, effective, and safe strategy to eliminate metastatic tumors in LNs is highly desired for clinical use. Carbon nanoparticles (CNs), as an LN tracer, have been widely used in the clinical setting. In addition, previous experiments have confirmed that CNs have good photoacoustic imaging and photothermal effects. In this study, we used CNs as a photothermal conversion material and drug carrier, poly(lactic-co-glycolic acid) (PLGA) as a film-forming material, and docetaxel as a chemotherapy drug to prepare multifunctional nanoparticles (DOC-CNPs). The prepared DOC-CNPs present as a black solution, which shows smooth spherical particles under light microscopy and transmission electron microscopy (TEM), and they have a good ability for liquid-gas phase transition, good dispersibility, high drug-loading capacity, and low cytotoxicity. In vitro, they can release drugs and inhibit tumor cells after laser irradiation. The photoacoustic (PA) signal intensity and the photothermal conversion efficiency increased with an increase in the concentration of DOC-CNPs. In vivo, after administration, the DOC-CNPs reached the LNs. After laser irradiation, the DOC-CNPs absorbed laser energy, and the temperature of the LNs increased high enough to achieve photothermal therapy under PA and ultrasound monitoring. Fracture of the DOC-CNPs was caused by the liquid-gas phase transition with the increased temperature, and the ruptured DOC-CNPs released docetaxel to achieve targeted chemotherapy. These findings suggested that DOC-CNPs can achieve precise treatment for metastatic LNs of breast cancer with PA and ultrasound visualization.


Percutaneous transluminal angioplasty of the carotid artery.
Percutaneous transluminal angioplasty (PTA) is being extensively applied to treat arteriosclerotic lesions. However, this application has not been widely accepted for the treatment of carotid artery stenosis. Successful attempts to relieve cerebral ischemia from extracranial carotid arterial stenosis by PTA are reported. Twenty-seven patients with arteriosclerotic stenosis, fibromuscular disease, and Takayasu carotid arterial stenosis were treated by PTA. All anatomic carotid stenotic lesions were corrected without any neurologic complication. Follow-ups ranged from 3 months to 4 years without recurrent symptoms in any patient. These results may suggest that some patients with cerebral ischemia secondary to extracranial carotid artery stenosis may be treated safely and effectively by PTA.


Reviewing the role of donepezil in the treatment of Alzheimer's disease.
Donepezil is a reversible, non-competitive piperidine-type acetylcholinesterase inhibitor (AChEI) that is structurally unique compared with other currently available AChEIs. It was developed as a symptomatic treatment to compensate for the progressive loss of cholinergic signal between neurons, a consequence of neuronal cell loss in the brains of patients with Alzheimer's disease (AD). Clinical trials conducted over the 15 years since the drug was first licensed and available for use in patients with mild to moderate AD (1997) have shown that donepezil is efficacious and well tolerated at all stages of AD, from patients with mild or moderate impairment to those with severe disease. The published literature contains nearly 2000 papers on donepezil, and more than 200 of these articles relate to randomized controlled clinical trials. Trials in patients with mild cognitive impairment (MCI) failed to meet all of their primary objectives, but provided insights into patient selection and the design of trials. Overall, more than a decade of donepezil research has gradually changed attitudes toward therapy of AD from a general belief that no clinically useful treatment exists to the present day understanding that symptomatic therapy may be effective across the spectrum of dementia stages.


[Heart rate control with nebivolol in patients with tachysystolic atrial fibrillation].
To find out whether selective beta-adrenoblocker nebivolol can be used for heart rate (HR) control in patients with chronic tachysystolic atrial fibrillation. Patients (n=20, 7 men, 13 women, age 47-79 years) with ischemic heart disease and permanent atrial fibrillation (duration 2.5 months - 11 years) admitted to a specialized clinic for diagnosis and treatment of cardiac arrhythmias. All patients had tachycardia throughout 24 hours despite therapy. Dosing of nebivolol: week 1 - 2.5 mg/day, week 2 7 5 mg/day. If after 2 weeks HR was considered inadequate the dose was increased up to 7.5 mg/day. Holter ECG was registered at baseline and in the end of weeks 1 and 2 of treatment. After 1 week of nebivolol (2.5 mg/day) HR decreased: day-time average - from 116.3+/-13.4 to 97.2+/-14.5, day-time minimal - from 78.1+/-13,5 to 71.4+/-8.2, day-time maximal - from 154.4+/-18.1 to 142.1+/-15.5; night-time average - from 83.6+/-7.1 to 76.3+/-7.14, night-time minimal - from 61.2+/-6.7 to 56.6+/-5.1, night-time maximal - from 93.5+/-10.5 to 88.2+/-10.8 bpm. After week 2 when patients received 5 mg/day of nebivolol their HR was: day-time average - 79.6+/-9,8, day-time minimal -65.2+/-7.7, day-time maximal - 128.7+/-12,2, night-time average - 69.9+/-7.6, night-time minimal - 53.1+/-4,7, night-time maximal - 80.8+/-10.1 bpm. In 2 patients (10%), interruption of nebivolol was required because of atrioventricular block in evening and nocturnal periods. Nebivolol effectively controlled HR in hospitalized patients with chronic atrial fibrillation due to ischemic heart disease. In most patients 5 mg /day was sufficient for attainment of acceptable HR.


Treatment of posttransplant lymphoceles: internal versus external drainage.
Six lymphoceles developed in 93 renal transplant recipients. Four were drained externally and two were drained internally. All patients with external drainage of lymphoceles experienced prolonged wound drainage with eventual contamination of the wound with pathogenic organisms. A technique of internal lymphocele drainage and its advantages was discussed.


The prediction of pouch of Douglas obliteration using offline analysis of the transvaginal ultrasound 'sliding sign' technique: inter- and intra-observer reproducibility.
What is the inter-/intra-observer agreement and diagnostic accuracy among gynaecological and non-gynaecological ultrasound specialists in the prediction of pouch of Douglas (POD) obliteration (secondary to endometriosis) at offline analysis of two-dimensional videos using the dynamic real-time transvaginal ultrasound (TVS) 'sliding sign' technique? The inter-/intra-observer agreement and diagnostic accuracy for the interpretation of the TVS 'sliding sign' in the prediction of POD obliteration was found to be very acceptable, ranging from substantial to almost perfect agreement for the observers who specialized in gynaecological ultrasound. Women with POD obliteration at laparoscopy are at an increased risk of bowel endometriosis; therefore, the pre-operative diagnosis of POD obliteration is important in the surgical planning for these women. Previous studies have used TVS to predict POD obliteration prior to laparoscopy, with a sensitivity of 72-83% and specificity of 97-100%. However, there have not been any reproducibility studies performed to validate the use of TVS in the prediction of POD obliteration pre-operatively. This was a reproducibility study which involved the offline viewing of pre-recorded video sets of 30 women presenting with chronic pelvic pain, in order to determine POD obliteration using the TVS 'sliding sign' technique. The videos were selected on real-time representative quality/quantity; they were not obtained from sequential patients. There were a total of six observers, including four gynaecological ultrasound specialists and two fetal medicine specialists. The study was conducted over a period of 1 month (March 2012-April 2012). The four gynaecological ultrasound observers performed daily gynaecological scanning, while the other two observers were primarily fetal medicine sonologists. Each sonologist viewed the TVS 'sliding sign' video in two anatomical locations (retro-cervix and posterior uterine fundus), i.e. 60 videos in total. The POD was deemed not obliterated, if 'sliding sign' was positive in both anatomical locations (i.e. anterior rectum/rectosigmoid glided smoothly across the retro-cervix/posterior fundus, respectively). If the 'sliding sign' was negative (i.e. anterior rectum/rectosigmoid did not glide smoothly over retro-cervix/posterior fundal region, respectively), the POD was deemed obliterated. Diagnostic accuracy and inter-observer agreement among the six sonologists was evaluated. The same sonologist was also asked to reanalyse the same videos, albeit in a different order, at least 7 days later to assess for intra-observer agreement. A separate analysis of the inter- and intra-observer correlation was also performed to determine the agreement among the four observers who specialized in gynaecological ultrasound. Cohen's κ coefficient <0 meant that there was poor agreement, 0.01-0.20 slight agreement, 0.21-0.40 fair agreement, 0.41-0.60 moderate agreement, 0.61-0.80 substantial agreement and 0.81-0.99 almost perfect agreement. Agreement (Cohen's κ) between all six observers for the interpretation of the 'sliding sign' for both sets of videos in both regions (retro-cervix and fundus) ranged from 0.354 to 0.927 (fair agreement to almost perfect agreement) compared with 0.630-0.927 (substantial agreement to almost perfect agreement) when only the gynaecological sonologists were included. The overall multiple rater agreement for the interpretation of the 'sliding sign' for both video sets and both regions was Fleiss' κ 0.454 (P-value <0.01) for all six observers and 0.646 (P-value <0.01) for the four gynaecological ultrasound specialists. The multiple rater agreement for all six or all four observers was higher for the retro-cervical region versus the fundal region (Fleiss' κ 0.542 versus 0.370 and 0.732 versus 0.560, respectively). The intra-observer agreement among the six observers for the interpretation of the 'sliding sign' and prediction of POD obliteration ranged from Cohen's κ 0.60-0.95 and 0.46-1.0 (P-value <0.01), respectively. After excluding the fetal medicine specialists, the intra-observer agreement for the interpretation of the 'sliding sign' and the prediction of POD obliteration ranged from Cohen's κ 0.71-0.95 and 0.67-1.0, respectively, indicating substantial to almost perfect agreement. When comparing the four gynaecological observers for the prediction of POD obliteration using the TVS 'sliding sign' (after excluding cases with the POD outcome classified as 'unsure' by the observers), the results for accuracy, sensitivity, specificity, positive and negative predictive value were 93.1-100, 92.9-100, 90.9-100, 77.8-100 and 97.7-100%, respectively. The 'gold standard' for the diagnosis of POD obliteration is laparoscopy; however, laparoscopic data were available only for 24 out of 30 (80%) TVS 'sliding sign' cases included in this study. Although this should not affect the inter- and intra-observer agreement findings, the ability to draw conclusions regarding the diagnostic accuracy of the TVS 'sliding sign' in the prediction of POD obliteration is somewhat limited. In addition, the diagnostic accuracy findings should be interpreted with the caveat that the cases classified as 'unsure' for the prediction of POD obliteration were excluded from the analysis. We have validated the dynamic real-time TVS 'sliding sign' technique for the prediction of POD obliteration, and this simple ultrasound-based test appears to have very acceptable inter-/intra-observer agreement for those who are experienced in gynaecological ultrasound. Given that women with POD obliteration at laparoscopy have an increased risk of bowel endometriosis and requirement for bowel surgery, the TVS 'sliding sign' test should be considered in the pre-operative imaging work-up for all women with suspected endometriosis, to allow for appropriate surgical planning. We believe the TVS 'sliding sign' technique may be easily learned by sonologists/sonographers who are familiar with performing gynaecological ultrasound, and that further studies are required to confirm the diagnostic accuracy of this new ultrasound technique amongst sonologists/sonographers with various levels of experience. This study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors and the authors declare no competing interests.


Effects of N2-O2 and CO2-O2 tensions on growth of fungi isolated from damaged flue-cured tobacco.
Ten fungi, Aspergillus niger, A. flavus, A. ochraceus, A. ruber, A. repens, A. amstelodami, Alternaria tenuis, Penicillium brevi-compactum, Cladosporium herbarum, and Chaetomium dolicotrichum, were isolated from moldy flue-cured tobacco and grown in various mixtures of N(2)-O(2) or CO(2)-O(2). A 1 to 5% concentration of O(2) in an N(2) atmosphere caused the greatest change in growth of the nine species, and a 10 to 20% concentration of O(2) for A. flavus. All species, except A. amstelodami and A. ruber, grew faster in air than in mixtures containing 10% O(2). High O(2) concentrations generally inhibited furrow production in the mycelial mats. In an atmosphere of 5 to 40% O(2) in the N(2) atmosphere, furrows formed in mycelial mats between 5 and 40% O(2) in the species except for A. ruber, A. repens, and A. amstelodami, which produced none in any concentration. As O(2) decreased below 20%, spore production was progressively decreased, colony color faded to white, and cleistothecia formation was suppressed. In CO(2)-O(2) mixtures radial growth of all species increased with each quantitative decrease of CO(2). All species except A. niger grew faster in air than in 10% CO(2). In contrast to N(2)-O(2) mixtures, the fungi formed furrows, sporulation and cleistothecial formation were suppressed, and colony color changed to white in higher O(2) concentrations.


Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen.
Hepatitis delta virus (HDV) replicates its genome in the nucleus of an infected cell. However, an unsolved problem has been the identification in the cytoplasm of a putative mRNA for the synthesis of the only virus-coded protein, the delta antigen. We now report the characterization of an 800-base RNA that is cytoplasmic, polyadenylated, and antigenomic and that should direct the translation of the delta antigen. This RNA was about 500 times less abundant than full-length genomic RNA. We mapped the predominant 5' terminus and also the 3' site at which the poly(A) is added. At a point 15 to 20 bases upstream of the poly(A) addition site is the sequence AAUAAA, which could have been used as a signal for the polyadenylation. When an infectious cDNA clone of the whole HDV genome was changed at this site to UUUAAA, the clone was no longer infectious and it was unable to direct the synthesis of the delta antigen. These findings provided additional evidence that the polyadenylated RNA was at least the predominant method for the expression of the delta antigen. Apparently the HDV RNA was processed as if it were a host mRNA polymerase II transcript, although this did not necessarily indicate that HDV RNA was transcribed with this enzyme.


Controllable magnetic doping of the surface state of a topological insulator.
A combined experimental and theoretical study of doping individual Fe atoms into Bi(2)Se(3) is presented. It is shown through a scanning tunneling microscopy study that single Fe atoms initially located at hollow sites on top of the surface (adatoms) can be incorporated into subsurface layers by thermally activated diffusion. Angle-resolved photoemission spectroscopy in combination with ab initio calculations suggest that the doping behavior changes from electron donation for the Fe adatom to neutral or electron acceptance for Fe incorporated into substitutional Bi sites. According to first principles calculations within density functional theory, these Fe substitutional impurities retain a large magnetic moment, thus presenting an alternative scheme for magnetically doping the topological surface state. For both types of Fe doping, we see no indication of a gap at the Dirac point.


Engineering of Syndiotactic and Isotactic Polystyrene-Based Copolymers via Stereoselective Catalytic Polymerization.
This contribution presents an updated overview of the different copolymers containing stereoregular polystyrene blocks. Special emphasis is placed on syndiospecific and isospecific copolymerization of styrene with co-monomers (ethylene and α-olefins, conjugated and non-conjugated dienes, styrene derivatives, etc.). The catalytic systems involved are described and the polymerization mechanisms are discussed. Alternative approaches (simultaneous, living, chain-transfer and graft copolymerization) and the resulting detailed structures and characteristics of the copolymers are also reported.


New Acridine-Based Tridentate Ligand for Ruthenium(II): Coordination with a Twist.
A new tridentate ligand based on acridine has been synthetized. The central acridine heterocycle bears two pyridine coordinating units at positions 4 and 5. The terdentate 2,7-di- tert-butyl-4,5-di(pyridin-2-yl)acridine (dtdpa) was then coordinated to a ruthenium(II) cation. The corresponding homoleptic complex could only be obtained where both ligands coordinate to the ruthenium in a fac fashion. Thus, a heteroleptic compound (2) was constructed in combination with a terpyridine ligand in order to constrain the ligand to adopt a mer geometry. Such a coordination imposes a dramatic twist on the acridine heterocycle, resulting in an unexpected photophysical behavior. The electrochemical and photophysical properties of both complexes were studied, and the molecular structure of 2 was determined by X-ray diffraction. The two compounds absorb at low energy wavelengths, and a very weak luminescence is detected only for complex 2 in the near-infrared region.


[Apparently opposite postulates of Ehrlich (Horror autotoxicus) and Metchnikoff (physiological autoimmunization) are not irreconcilable].
In 1900, the group from Metchnikoff suggested the concept of autoimmunization by demonstrating the presence of autoantibodies in normal conditions; which was opposed to the concept of horror autotoxicus raised by Ehrlich. Landsteiner's description of the transfusion compatibility rules and 50 year-later work from Burnett's and Medawar's groups lead to the clonal deletion theory as a general explanation of tolerance and autoimmunity. However, more recent work succeeded demonstrating that autoreactive B cells constitute a substantial part of the B-cell repertoire and that this autoreactive repertoire secretes the so-called natural autoantibodies (NAA) characterized by their broad reactivity mainly directed against very well conserved public epitopes. They fulfill the definition of an autoantibody since they are self-reactive, but they are not self-specific. As yet, NAA directed against determinants of polymorphism have not been reported. The presence of this repertoire in normal conditions challenges the clonal deletion theory as a unique explanation for self-tolerance. However, if we take into account that this autoreactive B-cell repertoire is not self-specific, this contradiction may not be a real one opposition. Indeed, the Lansteiner's rule that a subject belonging to group A will never produce anti-A antibodies and will always produce natural antibodies against the B-cell group, could never be challenged. Clonal deletion is probably accounting for this phenomenon. However, the serum of healthy adult individuals frequently exhibits low titers of anti-I antibodies, which is a precursor molecule of AB0 antigen system. The mechanism accounting for deletion of B cells directed against critical determinants like antigens A and B in the red blood cell system and allowing the production of autoantibodies against I remains elusive.


[Changes in systemic and pulmonary hemodynamics during an increase in lung volume].
15 anesthetized dogs were subjected to a gradual increase of the lungs volume by means of administration of the 50% gas mixture of oxygen and air. The exceeding of the lungs volume by 600 ml increased pressure in the caudal vein, reduced blood flow and systolic pressure in the heart ventricles. After administration of 800 ml of the gas, the systolic pressure started to raise in the right ventricle and achieved 36.8 mm Hg at the moment of intrathoracic pressure of 21.5 mm H2O and cessation of the minor circulation. Then the right ventricle augmented its mechanic activity inducing tachycardia, raise of the pressure up to 45.2 mm Hg and restoration of the lung circulation.


The Prevalence of Lewis, Lutheran, and P1 Antigens and Phenotypes in Southwestern Saudi Arabia.
Inherited hemoglobinopathies are common in Jazan Province, Saudi Arabia, and some patients may frequently require a blood transfusion. Therefore, the provision of compatible units using extended phenotypes is necessary to preclude the risk of alloimmunization. This study aimed to investigate the frequencies of the Lewis (LE), Lutheran (LU), and P1 antigens, as well as determine the prevalence of LE and LU phenotypes. This study collected 150 blood samples from Saudi Arabian anonymous volunteering blood donors at Prince Muhammed bin Nasser Hospital in Jazan Province, Saudi Arabia. Serotyping was performed using antigen profile-II based on gel card technology to determine LE, LU, and P1 antigens. The prevalence of antigens was as follows: Lea (n = 37, 24.6%), Leb (n = 87, 58%), Lua (n = 6, 4%), Lub (n = 150, 100%), and P1 (n = 120, 80%). Regarding the LE phenotypes, Le (a+b-) was 24.7%, Le (a-b+) was 58%, and Le (a-b-) was 17.3%. The frequencies of only observed LU phenotypes Lu (a-b+) and Lu (a+b+) were 96% and 4%, respectively. In summary, this study reports LE, LU, and P1 antigen prevalence. Moreover, LE and LU phenotype frequencies were investigated. This study may help establish a national database of blood group antigens in Jazan Province, Saudi Arabia. Additionally, it may provide better transfusion practice to avoid the alloimmunization risk.


Western equine and St. Louis encephalitis in man, California, 1945-1950.
A large group of etiologic agents, some known and some unknown, produce in man a clinical syndrome now labeled "infectious encephalitis."The separation, from this larger group, of single disease entities which cause similar clinical symptoms is possible, but calls for diagnostic acumen plus supporting laboratory evidence. Two etiologically specific entities, western equine encephalitis and St. Louis encephalitis, are frequently encountered in rather well-defined areas of California, the Central Valley and Imperial Valley; and there is a definite seasonal pattern of occurrence-June through October. There are certain guides that are helpful in differential diagnosis. Establishing a diagnosis on the basis of clinical evidence is difficult. Laboratory studies are of great importance not only for diagnosis in the individual case but for advancement of etiology. Specimens are worthless unless taken at proper intervals and submitted by methods described. It is probable that encephalitides caused by still unknown agents exist in California. The isolation and identification of new encephalitogenic viral agents will depend in large measure upon the submission by physicians of suitable specimens from patients with central nervous system disease in which the cause is obscure.


Nodular basal cell carcinoma in vivo vs in vitro. Establishment of pure cell cultures, cytomorphologic characteristics, ultrastructure, immunophenotype, biosynthetic activities, and generation of antisera.
In this study we developed an in vitro model of nodular basal cell carcinoma (BCC). We obtained pure cultures of BCC cells and compared the morphologic characteristics, ultrastructure, immunophenotype, and behavior of cultured tumor cells with those of their in vivo counterparts. Tumors were excised from patients undergoing Mohs micrographic surgery. We established 69 primary cell cultures from 32 patients with nodular BCC. Three cell types grew in primary cultures: fibroblasts, normal-appearing keratinocytes, and cells with dual (spindle and epithelioid) morphologic characteristics. Contaminating fibroblasts were removed using 0.125% trypsin-0.02% edetic acid, and normal-appearing keratinocytes were cornified and eliminated by temporarily increasing the concentration of calcium in the growth medium. The cells with dual morphologic characteristics remained intact and exhibited relentless growth in pure cultures. That these seemingly immortal cell strains represent true nodular BCC was demonstrated by (1) their biphasic morphologic characteristics and very slow cell growth rate, (2) their capability for anchorage-independent growth in soft agar, (3) their ultrastructural similarities to freshly excised nodular BCC, (4) their ability to generate antibodies selectively labeling nodular BCC tumor nests in vivo, and (5) their immunophenotypic similarities to BCC in vivo on more than 20 different cell markers. This study provides a simple technique for establishing pure cell cultures of nodular BCC and describes extensively the in vitro parameters of tumor cell growth. The striking differences in behavior of cultured tumor cells in the presence or absence of normal-appearing keratinocytes suggest that normal human epidermal keratinocytes can suppress the growth of BCC cells.


Psychosocial aspects of breast cancer treatment in Accra, Ghana.
To evaluate psychosocial influences and effects of breast cancer treatment. Cohort questionnaire survey. Surgical Outpatient Department, Korle Bu Teaching Hospital (KBTH), Accra, Ghana. Women previously treated for breast cancer, including those still on hormonal therapy. Perception of quality of treatment and psychosocial support; and patients' felt needs for alternative treatment. Eighty nine women treated one to 22 years previously were interviewed. The majority (86%) had mastectomy. Chemotherapy was the most unpleasant aspect of treatment in 58 (65.2%), and 27 (30.3%) were not warned about complications of treatment. Thirty eight (42.7%) reported being afraid (frightened or terrified) at the diagnosis; other reactions were shock, devastation, weeping and depression. Twenty two (24.7%) received no counselling and 15 (18.5%) did not have opportunity to express their fears of death 55 (61.8%), mastectomy/deformity 27 (30.3%) and financial incapability 23 (25.8%). Forty four (49.4%) used alternate 'treatment', mainly prayer camps (25 cases) and herbs (22 cases), before and during hospital treatment. Use of alternate treatment led to delays in treatment in 23 women. They had complaints about the care they received: lack of sympathy and emotional support (16 cases), lack of information and communication (13 cases), lack of counselling (9 cases) and slow processes (8 cases). Many patients utilise prayer camps and herbs leading to delays in treatment. Breast cancer patients in Ghana (West Africa) are not receiving satisfactory emotional support, communication and counseling. Adequate psychosocial interventions need to be implemented.


Role of Ca2+ and Na+ on luteinizing hormone release from the calf pituitary.
It has been proposed that gonadotropin-releasing hormone (GnRH) stimulates Ca2+ entry by activation of voltage-independent, receptor-mediated Ca2+ channels in the rat gonadotroph. Little work has been done on the role of calcium in GnRH-induced luteinizing hormone (LH) release in species other than the rat. Therefore, this study was done to compare the effects of agents that alter Ca2+ or Na+ entry on LH release from calf anterior pituitary primary cells in culture. GnRH (100 ng/ml), Ca2+ ionophore A23187 (2.5 microM), and the depolarizing agent ouabain (0.1-10 microM) all produced significant increases (P less than 0.05) in LH release; these effects were significantly reduced when the cells were preincubated with the organic Ca2+ channel blockers nifedipine (1-10 microM) and verapamil (1-10 microM) and with Co2+ (0.01-1 mM). The effect of ouabain was inhibited by tetrodotoxin (TTX; 1-10 nM) as well as by nifedipine at 0.1-10 microM. In contrast to its effect on rat pituitary LH release, TTX significantly inhibited GnRH-stimulated LH release at 1-100 nM. These results suggest that GnRH-induced LH release may employ Ca2+ as a second messenger in bovine gonadotrophs and support recent speculation that GnRH-induced Ca2+ mobilization may in part be voltage dependent.


Mapping of human and macaque sensorimotor areas by integrating architectonic, transmitter receptor, MRI and PET data.
The human and macaque sensorimotor cortex was subdivided into numerous areas by a correlative analysis based on cytoarchitectonics, myeloarchitecture and the distribution of transmitter receptors. Receptor densities and laminar distribution patterns differ not only between motor and somatosensory regions, but also between different areas within these regions of the cortex. Changes in receptor distribution often match architectonically defined borders. Receptor findings provide new criteria for a more detailed mapping in the human brain which cannot be achieved by cytoarchitectonic analysis alone. Morphological data on these areas were integrated with functional data from positron emission tomography (PET) on the basis of a recently developed computerised brain atlas. The central sulcus marks the border between (1) the agranular motor cortex with a generally low density of glutamatergic, muscarinic, GABAergic and serotoninergic receptors, and (2) the granular somatosensory cortex with higher densities of these receptors. Rostral to the primary motor cortex, 2 isocortical areas are found on the mesial cortex which probably represent the functionally defined supplementary motor areas (SMA) SMA-proper (caudally) and pre-SMA (rostrally). Below SMA-proper the areas 24d (macaque) and the caudal cingulate motor area cmc (human) are located in the cingulate sulcus. Both regions correspond to the 'posterior cingulate motor areas' of recent PET studies and to the posterior part of the agranular cingulate cortex of architectonic studies. Below pre-SMA the area 24c (macaque) and the rostral cingulate motor area cmr (human) are located in the cingulate sulcus; they correspond to the 'anterior cingulate motor areas' of recent PET observations and to the anterior part of the agranular cingulate cortex of architectonic studies. Homologous sensorimotor areas can be defined in both species on the basis of common architectonic features.


Studies of equivalence in clinical vaccine research.
The development of combination vaccines as well as the improved manufacture of vaccines have resulted in the need for clinical studies seeking equivalence or non-inferiority as investigators seek to demonstrate that combination vaccines achieve the same levels of efficacy, immunogenicity, and safety as their individual counterparts. Given the nature of the statistical analysis, studies of equivalence require particular attention to sample size. The current double-significance method of Neyman-Pearson attempts to address problems with equivalence testing, but it leads to very large sample sizes and illogical results. With such large samples, one can find a clinically trivial difference that is still statistically significant. The late Professor Alvan R. Feinstein proposed a more logical approach that would call for smaller, more workable sample sizes. Understanding the issues involved in sample size calculations for such studies is important to those who design clinical vaccine studies. The implications of the calculations will have far-reaching effects on the feasibility of the study such as availability of subjects, the success with recruitment, and the overall expenses. In fact, the feasibility issues may prevent the study being undertaken at all.


Propranolol HCL-loaded liposomes for intranasal delivery: in vitro and ex vivo evaluation of optimized formulation using design of experiments.
Aim: To develop a propranolol HCL-loaded liposomal nasal formulation for migraine prophylaxis. Materials & methods: Formulated the liposomes through thin layer hydration method and optimized via design of experiments (DOE). The prepared liposomes were characterized for particle size, zeta potential, PDI, drug entrapment and drug loading. Assessed for in vitro release kinetics, ex vivo permeability, histopathology and stability. Results: Optimized liposomes: 135.52 ± 5.87 nm, -19.9 ± 0.075 mV, 95.41 ± 0.05% entrapment, 43.37 ± 0.02% loading. Showed immediate (30.07 ± 2.09%) and sustained release (95.69 ± 4.58%) over 10 h. Enhanced permeation compared with controls; well-tolerated histopathologically. Conclusion: Liposomal formulation offers promise for intranasal propranolol HCL delivery in migraine prophylaxis, with stability under refrigeration.


Child nutritional status as screening tool for identifying undernourished mothers: an observational study of mother-child dyads in Mogadishu, Somalia, from November 2019 to March 2020.
Active screening of only pregnant and lactating mothers (PLMs) excludes other mothers of reproductive age susceptible to undernutrition. Our analysis evaluated if mothers presenting with wasted children were more likely to be undernourished themselves. The observational study enrolled mother and child dyads presenting to an outpatient facility in Mogadishu, Somalia, between November 2019 and March 2020. Trained nurses recorded lower extremity oedema for children aged 6-59 months, parity and gestational status for women aged 19-50 years and age, access to care, height/length, mid-upper arm circumference (MUAC) and weight for both. Weight-for-height z-score (WHZ) for children and body mass index (BMI) for mothers were calculated using standard procedures. Wasting was defined as WHZ <-2, MUAC <12.5 cm and/or presence of oedema for children. Undernutrition was defined as MUAC <23 cm for PLMs and BMI <18.5 kg/m2 for neither pregnant nor lactating mothers (non-PLMs). Four multivariable linear regression models were fit to evaluate maternal anthropometric indicators (BMI or MUAC) given child anthropometric indicators (MUAC or WHZ), adjusting for maternal age, parity and gestational status. A total of 93.6% (2142/2288) of enrolled dyads met inclusion criteria. Wasting was observed among 57.5% of children; 20.2% of pregnant mothers, 20.0% of lactating mothers and 7.95% of non-PLMs were undernourished. Models suggest significant, positive associations between child and maternal anthropometrics; a one-unit increase in WHZ and a 1 cm increase in child MUAC were associated with 0.22 kg/m2 (95% CI 0.22 to 0.24) and 0.19 kg/m2 (95% CI 0.16 to 0.21) increases in maternal BMI, respectively, and 0.20 cm (95% CI 0.18 to 0.22) and 0.24 cm (95% CI 0.23 to 0.25) increases in maternal MUAC, respectively. Adjusted R2 values were low (range 0.06-0.10). Undernutrition among non-PLMs illustrates the importance of expanding screening. However, while significant, the strength of association between mother and child anthropometrics does not support child nutritional status as a screening tool for identifying at-risk mothers.


Sml1p is a dimer in solution: characterization of denaturation and renaturation of recombinant Sml1p.
Sml1p is a small 104-amino acid protein from Saccharomyces cerevisiae that binds to the large subunit (Rnr1p) of the ribonucleotide reductase complex (RNR) and inhibits its activity. During DNA damage, S phase, or both, RNR activity must be tightly regulated, since failure to control the cellular level of dNTP pools may lead to genetic abnormalities, such as genome rearrangements, or even cell death. Structural characterization of Sml1p is an important step in understanding the regulation of RNR. Until now the oligomeric state of Sml1p was unknown. Mass spectrometric analysis of wild-type Sml1p revealed an intermolecular disulfide bond involving the cysteine residue at position 14 of the primary sequence. To determine whether disulfide bonding is essential for Sml1p oligomerization, we mutated the Cys14 to serine. Sedimentation equilibrium measurements in the analytical ultracentrifuge show that both wild-type and C14S Sml1p exist as dimers in solution, indicating that the dimerization is not a result of a disulfide bond. Further studies of several truncated Sml1p mutants revealed that the N-terminal 8-20 residues are responsible for dimerization. Unfolding/refolding studies of wild-type and C14S Sml1p reveal that both proteins refold reversibly and have almost identical unfolding/refolding profiles. It appears that Sml1p is a two-domain protein where the N-terminus is responsible for dimerization and the C-terminus for binding and inhibiting Rnr1p activity.


Analysis of outcome in carotid endarterectomy trials.
The trials for carotid endarterectomy have had a major impact on the practice of medicine. Beyond demonstrating the efficacy of this procedure for stroke prevention in certain patient cohorts, these studies have set a standard for the evaluation of surgical procedures by carefully planned, scientifically rigorous, prospective randomized controlled trials. In addition, data from these trials have been used to develop clinical guidelines (2, 12, 24), determine reimbursement policies, and establish criteria for perioperative morbidity. Concordance of methodology (especially primary outcome measures) among the various trials has enabled important valid comparisons between different patient cohorts. The benefit provided by carotid endarterectomy in most trials was so profound that the relative imprecision of stroke-related outcome measures did not significantly affect the findings. New outcome measures for stroke that evolved during these studies are being applied to ongoing trials for a variety of stroke therapies.


H-RAS V12-induced radioresistance in HCT116 colon carcinoma cells is heregulin dependent.
The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways following exposure to ionizing radiation is unknown. Loss of K-RAS D13 expression in HCT116 colorectal carcinoma cells blunted basal extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and c-Jun NH2-terminal kinase 1/2 activity. Deletion of the allele to express K-RAS D13 also enhanced expression of ERBB1, ERBB3, and heregulin but nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells but did not restore or alter basal c-jun NH2-terminal kinase 1/2 activity. In parental cells, radiation caused stronger ERK1/2 pathway activation compared with that of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which correlated with constitutive translocation of Raf-1 into the plasma membrane of parental cells. Inhibition of mitogen-activated protein kinase/ERK1/2, but not PI3K, radiosensitized parental cells. In H-RAS V12 cells, radiation caused stronger PI3K/AKT pathway activation compared with that of the ERK1/2 pathway, which correlated with H-RAS V12-dependent translocation of PI3K into the plasma membrane. Inhibition of PI3K, but not mitogen-activated protein kinase/ERK1/2, radiosensitized H-RAS V12 cells. Radiation-induced activation of the PI3K/AKT pathway in H-RAS V12 cells 2 to 24 hours after exposure was dependent on heregulin-stimulated ERBB3 association with membrane-localized PI3K. Neutralization of heregulin function abolished radiation-induced AKT activation and reverted the radiosensitivity of H-RAS V12 cells to those levels found in cells lacking expression of any active RAS protein. These findings show that H-RAS V12 and K-RAS D13 differentially regulate radiation-induced signaling pathway function. In HCT116 cells expressing H-RAS V12, PI3K-dependent radioresistance is mediated by both H-RAS-dependent translocation of PI3K into the plasma membrane and heregulin-induced activation of membrane-localized PI3K via ERBB3.


A pilot study using 99mTc to measure lead and platinum in the human kidney.
A pilot study has been conducted to investigate the hypothesis that the chemotherapeutic drug, cisplatinum, can mobilize skeletal lead. In vivo measurements of lead and platinum in the kidney of chemotherapy patients were performed with the technique of x-ray fluorescence, using 99mTc in a backscatter geometry. The results of the pilot study were inconclusive; the majority of patients exhibited no evidence of kidney lead at the level of system sensitivity, and negligible blood and urine lead levels.


Left Ventricular Global Function Index and the Impact of its Companion Metric.
Left ventricular (LV) global function index (LVGFI) has been introduced as a volume-based composite metric for evaluation of ventricular function. The definition formula combines stroke volume (SV), end-systolic volume (ESV), end-diastolic volume (EDV) and LV mass/density. Being a dimensionless ratio, this new metric has serious limitations which require evaluation at a mathematical and clinical level. Using CMRI in 96 patients we studied LV volumes, various derived metrics and global longitudinal strain (GLS) in order to further characterize LVGFI in three diagnostic groups: acute myocarditis, takotsubo cardiomyopathy and acute myocardial infarction. We also considered the LVGFI companion (C), derived from the quadratic mean. Additional metrics such as ejection fraction (EF), myocardial contraction fraction (MCF) and ventriculo-arterial coupling (VAC), along with their companions (MCFC and VACC) were calculated. All companion metrics (EFC, LVGFIC, MCFC, and VACC) showed sex-specific differences, not clearly reflected by the corresponding ratio-based metrics. LVGFI is mathematically coupled to both EF (with R = 0.86) and VAC (R = 0.87), which observation clarifies why these metrics not only share similar prognostic values but also identical shortcomings. We found that the newly introduced LVGFIC has incremental value compared to the single use of LVGFI, EF, or GLS, when characterizing the three patient groups.


Presence of apolipoprotein E epsilon4 allele predisposes to early onset of primary Sjogren's syndrome.
Apolipoprotein E (apoE) polymorphism plays a central role in lipid metabolism, but has recently also been suggested to regulate inflammation, as judged by levels of serum C-reactive protein (CRP). To establish whether polymorphism of the apoE genes affects susceptibility to primary Sjogren's syndrome (pSS), degree of inflammation or age of onset of pSS. ApoE genotype distribution and allelic frequencies were analysed using PCR and the TaqMan system in 63 Finnish Caucasian patients with pSS and in 64 healthy controls matched for sex, ethnic origin and area of residence. The clinical and immunological data on the pSS patients were analysed in relation to the apoE genotypes. There was no difference between pSS patients and controls in apoE genotype and allelic frequencies. The apoE epsilon4 allele was significantly associated with early onset of pSS in the entire population and in female patients (Kaplan-Meier log rank test, P = 0.0407 and P = 0.0168, respectively). The average age (+/- S.D.) of onset of pSS in all apoE epsilon4 allele carriers was 46 +/- 12 and in other genotypes it was 53 +/- 10 yr (P = 0.031, t-test). ApoE polymorphism was not associated with signs of inflammation evaluated by such markers as concentration of plasma CRP, plasma interleukin-6, plasma TNF-alpha, immunoglobulin G and haemoglobin, or leucocyte count or ESR. ApoE polymorphism does not affect susceptibility to pSS or levels of plasma inflammatory indices in patients with pSS. However, a clear association prevails between apoE epsilon4 and early onset of pSS.


Surgical and functional outcomes in bilateral exotropic Duane's retraction syndrome.
To evaluate the outcomes following surgery on patients with bilateral Duane's Retraction Syndrome (DRS) associated with exotropia or exophoria. Eleven consecutive patients with exotropic DRS were identified in a 10-year period. The case notes were reviewed, and data was analysed to evaluate the results following surgery. The preoperative and postoperative outcomes were evaluated for the angle of deviation in primary position, abnormal head posture, stereovision for near-fixation and horizontal ocular ductions. All patients had a significant improvement in their angle of deviation in primary position, and 82% had a residual angle within 10 prism dioptres of orthotropia/phoria (p<0.001). For those patients with abnormal head posture, 86% resolved or improved. The postoperative cumulative horizontal ocular ductions measured less in nine patients by an average of 1.5 units. Pre-existing near-stereovision improved in 83% of the patients by an average of 40″ arc. Surgery for bilateral exotropic DRS resulted in an improvement in the primary position angle and abnormal head posture. Patients demonstrated reduced cumulative horizontal ocular ductions restrictions and enhanced near-stereovision. This case series on exotropic bilateral DRS provides further evidence into successful postoperative surgical and functional outcomes.


Glucagon pharmacodynamics and modulation of sympathetic nerve and norepinephrine-induced constrictor responses in the superior mesenteric artery of the cat.
The aim of this study was to assess whether the pancreatic peptide glucagon was capable of inhibiting nerve- and norepinephrine-induced vasoconstrictor responses in the superior mesenteric artery of the anesthetized cat. Intra-arterial dose-response curves for glucagon and norepinephrine were analyzed by nonlinear regression to estimate the maximal response (maximal dilation, 163%; maximal constriction, 110%) in terms of percent change in superior mesenteric artery conductance and dose of glucagon or norepinephrine required to produce 50% of the maximal response (0.98 and 0.38 micrograms/kg/min, respectively). Constrictor responses (3-min duration) were only weakly inhibited by glucagon. Peak constrictor responses induced by low-dose i.a. infusions of norepinephrine were significantly inhibited (39%) by the high dose of glucagon, whereas the high-dose norepinephrine peak constrictor responses were unaffected by any dose of glucagon. Intermediate and high doses of glucagon significantly inhibited the low-frequency (2 Hz) nerve-induced peak constrictions (19% and 34%, respectively). The higher frequency (6 Hz) nerve-induced peak constrictor responses were not significantly affected by glucagon. Vascular escape from nerve- and norepinephrine-induced peak constrictor responses was not related to the degree of initial constriction nor were they affected by glucagon. Glucagon levels produced by our i.a. infusions were estimated to be well outside the pathophysiological range. We conclude that glucagon is not an effective inhibitor of constrictor responses in the superior mesenteric artery and is unlikely to have such an effect at physiological levels.


Evolution of Hox3 and ftz in arthropods: insights from the crustacean Daphnia pulex.
The Drosophila melanogaster genes zerknüllt (zen) and fushi tarazu (ftz) are members of the Hox gene family whose roles have changed significantly in the insect lineage and thus provide an opportunity to study the mechanisms underlying the functional evolution of Hox proteins. We have studied the expression of orthologs of zen (DpuHox3) and ftz (Dpuftz) in the crustacean Daphnia pulex (Branchiopoda), both of which show a dynamic expression pattern. DpuHox3 is expressed in a complex pattern in early embryogenesis, with the most anterior boundary of expression lying at the anterior limit of the second antennal segment as well as a ring of expression around the embryo. In later embryos, DpuHox3 expression is restricted to the mesoderm of mandibular limb buds. Dpuftz is first expressed in a ring around the embryo following the posterior limit of the mandibular segment. Later, Dpuftz is restricted to the posterior part of the mandibular segment. This is the first report of expression of a Hox3 ortholog in a crustacean, and together with Dpuftz data, the results presented here show that Hox3 and ftz have retained a Hox-like expression pattern in crustaceans. This is in accordance with the proposed model of Hox3 and ftz evolution in arthropods and allows a more precise pinpointing of the loss of ftz "Hox-like behaviour": in the lineage between the Branchiopoda and the basal insect Thysanura.


Fetal lip and primary palate: three-dimensional versus two-dimensional US.
To determine if three-dimensional (3D) ultrasonography (US) improves the ability to define the location and extent of facial clefting prenatally compared with two-dimensional (2D) US. Thirty-one fetuses suspected of having a facial cleft were examined prospectively with 2D and 3D US. Follow-up was performed in all fetuses. Twenty-eight fetuses had a cleft lip at birth. The location of the cleft lip was correctly identified in all fetuses with 3D US and in 26 of 28 with 2D US. Twenty-two fetuses had a cleft primary palate. Nineteen and nine of 22 cleft palates were identified by using 3D and 2D US, respectively. Three fetuses suspected of having a facial cleft at 2D US had a normal palate at 3D US and at birth. Three-dimensional US is useful to identify the location and extent of facial clefting. The advantages of 3D US are the following: (a) The face may be viewed in a standard orientation, (b) the defect may be viewed systematically by using an interactive display, and (c) the rendered image provides landmarks for the planar images. Patient decisions may be affected, since they can view the abnormality on a recognizable 3D rendered image.


A mesoporous ionic solid with 272 AuI 6AgI 3CuII 3 complex cations in a super huge crystal lattice.
Here, we report a unique mesoporous ionic solid (I) generated from a cationic AuI 6AgI 3CuII 3 dodecanuclear complex with d-penicillamine depending on the homochirality and crystallization conditions. I crystallizes in the cubic space group of F4132 with an extremely large cell volume of 2 171 340 Å3, containing 272 AuI 6AgI 3CuII 3 complex cations in the unit cell. In I, the complex cations are connected to each other through CH⋯π interactions in a zeotype framework, the topology of which is the same as that of the metal-organic framework in MIL-101, with similar but much larger two types of polyhedral pores with internal diameters of 38.2 Å and 49.7 Å, which are occupied by counter-anions and water molecules. Due to the cationic nature of the framework, I undergoes quick, specific exchanges of counter-anions while retaining its single crystallinity. This study realized the creation of a non-covalent mesoporous framework from a single complex salt, providing a conceptual advance in solid chemistry and material science.


Membrane type 4 matrix metalloproteinase (MMP17) has tumor necrosis factor-alpha convertase activity but does not activate pro-MMP2.
Membrane type 4 matrix metalloproteinase (MT4-MMP) shows the least sequence homology to the other MT-MMPs, suggesting a distinct function for this protein. We have isolated a complete cDNA corresponding to the mouse homologue which includes the signal peptide and a complete pro-domain, features that were lacking from the human form originally isolated. Mouse MT4-MMP (mMT4-MMP) expressed in COS-7 cells is located at the cell surface but does not show ability to activate pro-MMP2. The pro-catalytic domain was expressed in Escherichia coli as insoluble inclusions and active enzyme recovered after refolding. Activity of the isolated catalytic domain against synthetic peptides commonly used for MMP enzyme assays could be inhibited by TIMP1, -2, and -3. The recombinant mMT4-MMP catalytic domain was also unable to activate pro-MMP2 and was very poor at hydrolyzing components of the extracellular matrix with the exception of fibrinogen and fibrin. mMT4-MMP was able to hydrolyze efficiently a peptide consisting of the pro-tumor necrosis factor alpha (TNFalpha) cleavage site, a glutathione S-transferase-pro-TNFalpha fusion protein, and was found to shed pro-TNFalpha when co-transfected in COS-7 cells. MT4-MMP was detected by Western blot in monocyte/macrophage cell lines which in combination with its fibrinolytic and TNFalpha-converting activity suggests a role in inflammation.


Evaluation of protective efficacy conferred by a recombinant Mycobacterium bovis BCG expressing a fusion protein of Ag85A-ESAT-6.
We previously constructed a recombinant bacille Calmette-Guérin (rBCG-AE) strain that could express a fused Ag85A-ESAT-6 protein. That study suggested that the rBCG-AE strain was able to induce a higher titer of antibody and elicit a more long-lived and stronger Th1-type cellular immune responses than the parental BCG strain, the rBCG-A strain (i.e., expressing Ag85A), or the rBCG-E strain (i.e., expressing ESAT-6). In the current study, we further investigated the strain's protective efficacy against Mycobacterium tuberculosis H37Rv infection in BALB/c mice through evaluating organ bacterial loads, lung histopathology, lung immunohistochemistry, and net weight gain or loss by using conventional BCG, rBCG-A, and rBCG-E as the controls. From the 3rd to 9th weeks after the challenge infection, the bacterial counts were significantly lower in tissues (e.g., spleen and lung tissues) in the mice immunized with rBCG-AE than in the control group, but were higher than the counts in the BCG group. The pathological damage in the lung tissues of the rBCG-AE group gradually improved from the 6th to 9th weeks after being infected with M. tuberculosis H37Rv, but the score of pathological changes in the rBCG-AE group was obviously higher than the score in the BCG group. There was no difference in the percentage of IFN-γ and iNOS positive cells in the lung tissues of the rBCG-AE and BCG groups. The results suggest that rBCG-AE can not promote protective efficacy against M. tuberculosis H37Rv infection, compared to the BCG vaccine.


Cognitive function and plasma BDNF levels among manganese-exposed smelters.
To explore the potential dose-response relationship between manganese (Mn) exposure and cognitive function and also plasma brain-derived neurotrophic factor (BDNF) levels in occupational Mn exposure workers. A total 819 workers were identified from our Mn-exposed workers, and 293 control workers were recruited in the same region. All exposed workers were divided into three groups based on Mn cumulative exposure index. The Montreal Cognitive Assessment (MoCA) test was applied to estimate cognitive function for all subjects. Plasma BDNF levels were determined by ELISA in 248 selected exposed workers and 100 controls. Mn-exposed workers had significantly lower MoCA scores than those in the control group (25.62 ± 0.25): those in high-exposure group had the lowest scores (21.33 ± 0.32), compared with the intermediate-exposure group (23.22 ± 0.30) and low-exposure group (23.57 ± 0.23). Mn exposure levels were inversely associated with MoCA total scores, all p<0.05. A positive correlation was found between plasma BDNF levels and MoCA total scores (r=0.278, p<0.01). Moreover, compared with the control group (288.7 ± 181.7 pg/mL), BDNF levels were lower in the high-exposure group (127.5 ± 99.8 pg/mL), and in the intermediate-exposure (178.2 ± 138.1 pg/mL) and low-exposure groups (223.4 ± 178.3 pg/mL). Additionally, plasma BDNF levels decreased significantly as Mn exposure levels increased (ptrend<0.01). Mn exposure may be associated with decreased plasma BDNF levels and cognition impairment in this large cross-sectional study.


New experiences with antilymphocyte globulin in human organ transplantation.
This is a retrospective analysis of 100 consecutive primary renal allotransplantations using cadaver kidneys exclusively. Seven patients were sensitive to horse globulin and were therefore not treated with ALG. In all the other 93 patients ALG was given for the first postoperative weeks in addition to standard immunosuppressive therapy. In this group, the one year survival with functioning primary transplan is 73%. The control group is also doing fairly well (5 out of 7 surviving), but it is too small for statistical analysis. Several possible explanations are given for the divergent results in this field.


Cortical plasticity of spatial stimulus-response associations: electrophysiological and behavioral evidence.
Right-handed subjects tend to respond faster to stimuli presented in the visual hemifield that spatially corresponds to the responding hand. In a typical Simon task, response is based on a non-spatial salient feature of the stimulus (e.g. color) whereas its position must be ignored. However, the spatial position of the stimulus interferes with the processing of the salient characteristic. Subjects are significantly faster when stimulus side and response side correspond (corresponding condition) than when they do not (non-corresponding condition). We have previously shown with behavioral experiments that, when subjects practice reversed contingencies (that is, spatially incompatible trials) in a session preceding the Simon task, they show a long-term retention of these associations, resulting in the disappearance of the latency cost typically observed in non-corresponding trials. Here we show, by means of the lateralized readiness potential, that the neural correlate of such behavioral plasticity is an increase in premotor cortex activation during preparation of non-corresponding responses. This effect showed a marked left-right asymmetry which suggests an important role of subjects' handedness. Our results demonstrate that humans can learn in a single session to reverse relatively stable stimulus-response associations.


Linguistic Constraints on Statistical Word Segmentation: The Role of Consonants in Arabic and English.
Statistical learning is often taken to lie at the heart of many cognitive tasks, including the acquisition of language. One particular task in which probabilistic models have achieved considerable success is the segmentation of speech into words. However, these models have mostly been tested against English data, and as a result little is known about how a statistical learning mechanism copes with input regularities that arise from the structural properties of different languages. This study focuses on statistical word segmentation in Arabic, a Semitic language in which words are built around consonantal roots. We hypothesize that segmentation in such languages is facilitated by tracking consonant distributions independently from intervening vowels. Previous studies have shown that human learners can track consonant probabilities across intervening vowels in artificial languages, but it is unknown to what extent this ability would be beneficial in the segmentation of natural language. We assessed the performance of a Bayesian segmentation model on English and Arabic, comparing consonant-only representations with full representations. In addition, we examined to what extent structurally different proto-lexicons reflect adult language. The results suggest that for a child learning a Semitic language, separating consonants from vowels is beneficial for segmentation. These findings indicate that probabilistic models require appropriate linguistic representations in order to effectively meet the challenges of language acquisition.


Identification of the cydC locus required for expression of the functional form of the cytochrome d terminal oxidase complex in Escherichia coli.
The aerobic respiratory chain of Escherichia coli contains two terminal oxidases which are differentially regulated. The cytochrome o complex predominates under growth conditions of high aeration, whereas the cytochrome d complex predominates when the oxygen tension is low. Either terminal oxidase will support aerobic growth. The goal of the work presented in this paper was to identify genes required for the expression of the functional form of the cytochrome d complex, other than the genes encoding the polypeptide components of the oxidase complex (cyd locus). A strain lacking the cytochrome o complex (cyo mutant strain) was mutagenized by using a lambda-Mu hybrid hopper bacteriophage, lambda placMu53, which inserts randomly into the chromosome and carries a kanamycin resistance marker. Strains were isolated and examined which were unable to grow aerobically, i.e., which lacked functional cytochrome d complex, and which could not be complemented by introduction of the cyd gene on F-prime episomes. One strain was selected for characterization. The phage insert was mapped to min 18.9 on the genetic linkage map, defining a new genetic locus, cydC. Evidence described in the text suggests that the gene product is probably required for the synthesis of the unique heme d component of the cytochrome d complex.


[Endobronchial metastasis from renal cell carcinoma resected 9 years before; report of a case].
A 68-year-old man, who had undergone a left nephrectomy for a clear cell type renal cell carcinoma (RCC) in June 1995 and then received interferon therapy till March 1997, was admitted with dyspnea in June 2004. Chest X-ray showed atelectasis of the left lower lung lobe and chest computed tomography revealed a polypoid mass in the left lower bronchus. He was diagnosed with a pulmonary metastasis of a RCC by transbronchial biopsy. We considered it a slow growing type of RCC because of the long disease free interval (DFI). A left lower lobectomy with bronchoplasty was carried out. However, 6 month after the operation, a new lesion has occurred near the portion of the broncho-anastmosis and multiple metastases have developed in the right lung.


Complete sequence and organization of the Serratia marcescens biotin operon.
The nucleotide sequence of the biotin (bio) operon of wild-type Serratia marcescens Sr41 was determined. Five ORFs were identified to encode BioA (7,8-diaminopelargonic acid aminotransferase), BioB (biotin synthase), BioF (7-keto-8-aminopelargonic acid synthase), BioC (an enzyme catalysing the synthesis of pimeloyl-CoA) and BioD (dethiobiotin synthase), in this order. The operon was deduced to be transcribed divergently to the left into bioA and to the right into the bioBFCD genes. The promoters and a common predicted operator for both bioA and bioBFCD genes were located between the bioA and bioB genes. The predicted amino acid sequences of these enzymes were similar to the sequences of the corresponding enzymes of Escherichia coli. Analysis of expression of the lacZ structural gene fused with the bioA and bioB promoters revealed that the biotin operon was subject to biotin-mediated feedback repression.


TRAF molecules in cell signaling and in human diseases.
The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of intracellular proteins were originally identified as signaling adaptors that bind directly to the cytoplasmic regions of receptors of the TNF-R superfamily. The past decade has witnessed rapid expansion of receptor families identified to employ TRAFs for signaling. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), T cell receptor, IL-1 receptor family, IL-17 receptors, IFN receptors and TGFβ receptors. In addition to their role as adaptor proteins, most TRAFs also act as E3 ubiquitin ligases to activate downstream signaling events. TRAF-dependent signaling pathways typically lead to the activation of nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). Compelling evidence obtained from germ-line and cell-specific TRAF-deficient mice demonstrates that each TRAF plays indispensable and non-redundant physiological roles, regulating innate and adaptive immunity, embryonic development, tissue homeostasis, stress response, and bone metabolism. Notably, mounting evidence implicates TRAFs in the pathogenesis of human diseases such as cancers and autoimmune diseases, which has sparked new appreciation and interest in TRAF research. This review presents an overview of the current knowledge of TRAFs, with an emphasis on recent findings concerning TRAF molecules in signaling and in human diseases.


In vivo reflectance measurement of optical properties, blood oxygenation and motexafin lutetium uptake in canine large bowels, kidneys and prostates.
Motexafin lutetium (MLu) is a second-generation photosensitizer for photodynamic therapy (PDT) of cancer. We have developed and applied a diffuse optical reflectance spectrometer for in vivo measurement of MLu uptake, optical properties, haemoglobin concentration and haemoglobin oxygen saturation in normal canine large bowels, kidneys and prostates. The probe consists of a broadband fibre-optic-coupled light source and detector fibres placed at various distances from the source fibre to collect reflected light. An analysis based on the diffusion approximation of the photon transport equation was used to recover tissue optical properties from the reflectance measurements. The instrumentation and analysis methods were validated using measurements from homogeneous, highly scattering phantoms with known MLu concentrations. The same techniques were then used to estimate chromophore concentrations of normal canine large bowels, kidneys and prostates. We estimated (mean (standard deviation)) total haemoglobin concentrations of 119 (25), 340 (92) and 51 (11) microM in the large bowels, kidneys and prostates of four dogs, respectively; tissue blood oxygen saturations in these same organs were 75 (15), 76 (21) and 74 (16) per cent, respectively. Tissue MLu concentrations (mg l(-1)) were estimated from data taken 3.5 h after injection of a 2 mg kg(-1) injected dose; data from three dogs gave concentrations of 2.4 (0.4) in large bowels, 6.8 (1.3) in kidneys and 2.2 (1.1) in prostates. The reduced scattering coefficients, mu's, estimated for large bowels, kidneys and prostates at 730 nm were, respectively: 10.1 (1.3), 19.6 (4.0) and 12.7 (0.6) cm(-1). We observed significant variability in MLu uptake, tissue scattering and haemoglobin concentration between organs and even between the same organ in different dogs. This class of in situ optical property measurement may be desirable to individualize PDT drug and light delivery.


Diagnostic problems of leptomeningeal lymphoma. A report of 3 cases.
Three cases are presented in which occult lymphoreticular malignant tumour spread to the spinal and cranial subarachnoid spaces inducing a problematic neurological illness characterised by poorly localised neuralgic pain, slowly progressive paresis and, in 2 patients, papilloedema with computed tomographic evidence of ventricular dilatation. Despite intensive investigations, diagnosis was only achieved at autopsy. A progressive disturbance of spinal and cranial nerve function should direct the attention of the clinician to the possibility of diffuse meningeal involvement by a malignant or inflammatory process.


Correlation of three-dimensional structures with the antibacterial activity of a group of peptides designed based on a nontoxic bacterial membrane anchor.
To understand the functional differences between a nontoxic membrane anchor corresponding to the N-terminal sequence of the Escherichia coli enzyme IIA(Glc) and a toxic antimicrobial peptide aurein 1.2 of similar sequence, a series of peptides was designed to bridge the gap between them. An alteration of a single residue of the membrane anchor converted it into an antibacterial peptide. Circular dichroism spectra indicate that all peptides are disordered in water but helical in micelles. Structures of the peptides were determined in membrane-mimetic micelles by solution NMR spectroscopy. The quality of the distance-based structures was improved by including backbone angle restraints derived from a set of chemical shifts ((1)H(alpha), (15)N, (13)C(alpha), and (13)C(beta)) from natural abundance two-dimensional heteronuclear correlated spectroscopy. Different from the membrane anchor, antibacterial peptides possess a broader and longer hydrophobic surface, allowing a deeper penetration into the membrane, as supported by intermolecular nuclear Overhauser effect cross-peaks between the peptide and short chain dioctanoyl phosphatidylglycerol. An attempt was made to correlate the NMR structures of these peptides with their antibacterial activity. The activity of this group of peptides does not correlate exactly with helicity, amphipathicity, charge, the number of charges, the size of the hydrophobic surface, or hydrophobic transfer free energy. However, a correlation is established between the peptide activity and membrane perturbation potential, which is defined by interfacial hydrophobic patches and basic residues in the case of cationic peptides. Indeed, (31)P solid state NMR spectroscopy of lipid bilayers showed that the extent of lipid vesicle disruption by these peptides is proportional to their membrane perturbation potential.


Macronutrient analysis of donor human milk labelled as 24 kcal/oz.
To measure the macronutrient content (MNC) of donor human milk labelled as 24 kcal/oz ("high-calorie DHM," hcDHM), compare to bank-labelled MNC, and examine variability of hcDHM MNC among milk banks. MNC was measured with near-infrared spectroscopy for 75 convenience samples from five milk banks collected during September 2016-July 2017. Concordance of measured MNC with labelled values was evaluated using three different thresholds: within ±20%, similar to FDA labelling standards for class II nutrients in foods; ±10%; and ±5%. Protein and caloric content differed significantly between measured and labelled values and varied significantly among milk banks. Measured caloric content ranged from 16.50 to 30.27 kcal/oz, with 89.3% of hcDHM samples within ±20%, 58.7% within ±10%, and 18.7% within ±5% of labelled content. MNC of hcDHM used in clinical practice shows variation that may result in differences from desired diet. The clinical implications of such differences are unexplored.


Decrease in muscle glucose transporter number in chronic physical inactivity in rats.
In this study, whole body insulin action on glucose uptake and muscle glucose transporter number of rats subjected to 14 days of physical inactivity conditions was examined. Unlike other suspension and denervation models of muscle disuse, this physical inactivity model allows voluntary contractile activity with minimal stress. Minimal depression of body weight gain and significant depression of gastrocnemius muscle growth were observed compared with that of control rats after 14 days of physical inactivity. The whole body insulin sensitivity and responsiveness were determined by the euglycemic clamp technique, with 1.4, 3.6, and 14 mU insulin.kg-1.min-1 perfusion and 2-deoxy-D-[3H]glucose incorporation. The rates of glucose disposal were the same in the restrained rats as in the controls with the 1.4 and 3.6 mU insulin perfusion; however, glucose disposal significantly decreased with 14 mU insulin perfusion. 2-Deoxy-D-[3H]glucose uptake into the gastrocnemius muscle was higher in the control rats than in the physically inactive rats. Glucose transporters in the gastrocnemius and quadriceps muscles, measured by means of the D-glucose-inhibitable cytochalasin B binding assay, were significantly decreased in number in the physically inactive rats. These findings suggest that the decrease in whole body glucose uptake might in part be explained by the decreases in the total glucose transporter number in muscles.


Usefulness of improvement in walking distance versus peak oxygen uptake in predicting prognosis after myocardial infarction and/or coronary artery bypass grafting in men.
Information is limited on the influence of a change in fitness and/or physical activity on mortality in cardiac patients who undergo exercise rehabilitation. This was studied in 6,956 men (4,713 with myocardial infarctions, 2,243 who underwent coronary bypass surgery) completing a 12-month walking-based training regimen and followed for a median of 9 years (range 4 to 26; 67,820 patient-years). Peak oxygen uptake (VO2peak) was measured at the beginning and the end of the program, and walking distance and pace were recorded weekly. These and other pertinent data were entered into a Cox proportional-hazards model and tested for associations with time to cardiac and all-cause death. In total, 2,016 deaths were recorded (737 cardiac, 1,279 all-cause). The mean increase in VO2peak was 4.9 ml/kg/min (95% confidence interval [CI] 4.7 to 5.0, p <0.0001), and the mean increase in distance walked was 2.1 mi (95% CI 2.0 to 2.1, p <0.0001). Increase in VO2peak was significant on univariate analysis (hazard ratio [HR] 0.98) but not on multivariate analysis. Distance increase was a significant predictor of cardiac and all-cause death on multivariate analysis, with each 1-mi improvement conferring a 20% reduction in cardiac death (HR 0.80, 95% CI 0.71 to 0.87, p <0.0001). When categorized into groups of <1.3 (referent), 1.3 to 2.8, and >2.8 mi, increased walking distance of 1.3 to 2.8 and of >2.8 mi yielded 24% (HR 0.76, 95% CI 0.62 to 0.92, p = 0.005) and 48% (HR 0.52, 95% CI 0.40 to 0.68, p <0.0001) reductions in cardiac death, respectively. In conclusion, in men who underwent an exercise rehabilitation program, improvement in walking distance was a strong independent predictor, and a greater guide to prognosis, than gains in VO2peak.


Angioplasty versus stenting for infrapopliteal arterial lesions in chronic limb-threatening ischaemia.
Chronic limb-threatening ischaemia (CLTI) is a manifestation of peripheral arterial disease (PAD) that includes chronic ischaemic rest pain or ischaemic skin lesions, ulcers, or gangrene for longer than two weeks. The severity of the disease depends on the extent of arterial stenosis and the availability of collateral circulation. Treatment for CLTI aims to relieve ischaemic pain, heal ischaemic ulcers, prevent limb loss, improve quality of life, and prolong survival. CLTI due to occlusive disease in the infrapopliteal arterial circulation (below-knee circulation) can be treated via an endovascular technique by a balloon opening the narrowed vessel, so called angioplasty, with or without the additional deployment of a scaffold made of metal alloy or other material, so called stenting. Endovascular interventions in the infrapopliteal vasculature may improve symptoms in patients with CLTI by re-establishing in-line blood flow to the foot. Controversy remains as to whether a balloon should be used alone to open the vessel, or whether a stent should also be deployed. To determine the efficacy and safety of percutaneous transluminal angioplasty (PTA) alone versus PTA with stenting of infrapopliteal arterial lesions (anterior tibial artery, posterior tibial artery, fibular artery (formerly known as peroneal artery), and common tibioperoneal trunk) for patients with chronic limb-threatening ischaemia (CLTI). The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and AMED databases, as well as World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 25 June 2018. We applied no language restrictions. We planned to include randomised or quasi-randomised controlled trials comparing PTA versus PTA with a stent and including patients aged 18 years or over with CLTI. We defined CLTI as Fontaine stage III (ischaemic rest pain) and IV (ischaemic ulcers or gangrene) or consistent with Rutherford category 4 (ischaemic rest pain), 5 (minor tissue loss), and 6 (major tissue loss), with stenotic (> 50% luminal loss) or occluded infrapopliteal artery, including tibiofibular trunk, anterior tibial artery, posterior tibial artery, and fibular artery. We included all types of stents irrespective of design (e.g. bare-metal, drug-eluting, bio-absorbable). Two review authors (CC-TH and GNCK) independently selected suitable trials, assessed trial quality, and extracted data. An additional third review author (MLvD) assessed trial quality and, when necessary, acted as arbiter for study selection and data extraction. Outcomes included technical success of the procedure, procedural complications, patency, major amputation, and mortality. We assessed the quality of evidence using the GRADE approach. We included in the review seven trials with 542 participants. One trial randomised limbs to undergo PTA alone or PTA with stent placement, and the remaining studies randomised participants. Five trials with 476 participants show that the technical success rate was greater in the stent group than in the angioplasty group (odds ratio (OR) 3.00, 95% confidence interval (CI) 1.14 to 7.93; 476 lesions; 5 studies; I² = 23%). Meta-analysis of three eligible trials with 456 participants did not show a clear difference in short-term (within six months) patency between infrapopliteal arterial lesions treated with PTA and those treated with PTA and stenting (OR 0.88, 95% CI 0.37 to 2.11; 456 lesions; 3 studies; I² = 77%). Results also did not show clear differences between treatment groups in procedure complication rate (OR 0.87, 95% CI 0.01 to 53.60; 360 participants; 5 studies; I² = 85%), rate of major amputations at 12 months (OR 1.34, 95% CI 0.56 to 3.22; 306 participants; 4 studies; I² = 0%), and rate of mortality at 12 months (OR 0.71, 95% CI 0.43 to 1.17; 497 participants; 6 studies; I² = 0%). Heterogeneity between studies was high for the outcomes procedure complications and primary patency. The overall methodological quality of the trials included in this review was moderate due to selection and performance bias. Studies used different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication. We downgraded the certainty of the overall evidence for all outcomes by one level to moderate due to inconsistency of results across studies and large confidence intervals (small numbers of trials and participants). Trials show that the immediate technical success rate of restoring luminal patency is higher in the stent group but reveal no clear differences in short-term patency at six months between infrapopliteal arterial lesions treated with PTA with stenting versus those treated with PTA without stenting. We ascertained no clear differences between groups in periprocedural complications, major amputation, and mortality. However, use of different regimens for pretreatment and post-treatment antiplatelet/anticoagulant medication and the duration of its use within and between trials may have influenced the outcomes. Limited currently available data suggest that high-quality evidence is insufficient to show that PTA with stent insertion is superior to use of standard PTA alone without stenting for treatment of infrapopliteal arterial lesions. Further studies should standardise the use of antiplatelets/anticoagulants before and after the intervention to improve the comparability of the two treatments.


Control of the cyclic GMP phosphodiesterase of frog photoreceptor membranes.
The light-activated cyclic GMP phosphodiesterase (PDE) of frog photoreceptor membranes has been assayed in isolated outer segments suspended in a low-calcium Ringer's solution. Activation occurs over a range of light intensity that also causes a decrease in the permeability, cyclic GMP levels, and GTP levels of isolated outer segments. At intermediate intensities, PDE activity assumes constant intermediate values determined by the rate of rhodopsin bleaching. Washing causes an increase in maximal enzyme activity. Increasing light intensity from darkness to a level bleaching 5 x 10(3) rhodopsin molecules per outer segment per second shifts the apparent Michaelis constant (Km) from 100 to 900 microM. Maximum enzyme velocity increases at least 10-fold. The component that normally regulates this light-induced increase in the Km of PDE is removed by the customary sucrose flotation procedures. The presence of 10(-3) M Ca++ increases the light sensitivity of PDE, and maximal activation is caused by illumination bleaching only 5 x 10(2) rhodopsin molecules per outer segment per second. Calcium acts by increasing enzyme velocity while having little influence on Km. The effect of calcium appears to require a labile component, sensitive to aging of the outer segment preparation. The decrease in the light sensitivity of PDE that can be observed upon lowering the calcium concentration may be related to the desensitization of the permeability change mechanism that occurs during light adaptation of rod photoreceptors.


A Classification of Healthcare Facilities: Toward the Development of Energy Performance Benchmarks for Day Surgery Centers in Australia.
In the literature, there is no consistent classification of healthcare facilities. In order to benchmark, assess, and compare the environmental performance of these buildings, it is important to clearly identify the typology within the scope of a particular research. This article identifies the different typologies within the healthcare sector, particularly in Australia, with the aim of the development of energy performance benchmarks for day surgery/procedure centers. Healthcare buildings encompass a wide range of facilities. They all share the same purpose of healing and offering a health service for patients. However, they vary significantly in terms of patient type and service provided. These buildings consume a considerable amount of energy, and as a result of the different designs and sizes, their pattern of energy consumption varies. The research used a systematic review of the literature to determine how the term "healthcare facility" has been employed in different contexts. In order to better understand the differences in healthcare facilities, definitions and the origin of hospitals and healthcare facilities are introduced and a framework for the classification of healthcare facilities and hospitals is proposed. Healthcare facilities are classified into the following six categories: patient type, care provided, management and ownership, level of care, facility size, and location. Based on these classifications, a categorization for the studies of energy performance in healthcare is introduced. This study provides a basis for assessment and comparison for a particular healthcare building typology that will assist researchers working in the field of design and energy assessment of healthcare facilities.


Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
Selective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas. A total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee. A total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups. Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk.


[The current aspects of diagnosis and expertise in flight personnel with gallstones].
The paper discusses the modern aspects of diagnosis and expertise of pilots suffering from gall-stones. The present-day methods were used to examine 196 pilots of different aviation categories (helicopter in the main). Semiotic signs of different variations of gall-stones are studied, comparative characteristics of diagnostic methods are demonstrated, more effective algorithms of examination are elaborated. It is shown that in the radio-clinical examination the ultrasonic investigation holds the lead in the diagnostic algorithm enabling in the shortest way early and correct detection of concretions in the biliary tracts. Viscous putty-like bile in the gall bladder found during preventive monitoring is an unfavourable sign calling for correction of diet, motor activity and medicamentous therapy.


Dexamethasone phosphate and penetratin co-eluting contact lenses: a strategy to enhance ocular drug permeability.
Contact lenses (CLs) have been suggested as drug delivery platforms capable of increasing the drug residence time on the cornea and therefore its bioavailability. However, when targeting the posterior segment of the eye, the drug released from CLs still encounters the barrier effect of the ocular tissues, which considerably reduces the efficacy of administration. This work aims at the development of CLs able to simultaneously deliver an anti-inflammatory drug (dexamethasone sodium phosphate) and a cell-penetrating peptide (penetratin), the latter acting as a drug carrier across the tissues. Hydroxyethyl methacrylate (HEMA)-based hydrogels were functionalized with acrylic acid (AAc) and/or aminopropyl methacrylamide (APMA) to serve as CL materials with increased affinity for the drug and peptide. APMA-functionalized hydrogels sustained the dual release for 8h, which is compatible with the wearing time of daily CLs. Hydrogels demonstrated suitable light transmittance, swelling capacity and in vitro biocompatibility. The anti-inflammatory activity of the drug was not compromised by the presence of the peptide nor by sterilization. The ocular distribution of the drug after 6h of CL wearing was evaluated in vivo in rabbits and revealed that the amount of drug in the cornea and aqueous humor significantly increased when the drug was co-delivered with penetratin.


Climatic and Seasonal Circumstances of Hypertensive Intracerebral Hemorrhage in a Worldwide Cohort.
Numerous studies have investigated the influence of meteorologic factors and seasons on the incidence of spontaneous intracerebral hemorrhage (ICH) with ambiguous results. In the present study, data from a large, international multicenter trial in patients with ICH were used to identify seasonal and meteorologic determinants for hypertensive-ICH with greater applicability. Patients were grouped according to the presumptive ICH cause, that is, hypertensive when located in the basal ganglia brain stem as well as cerebellum and nonhypertensive when located lobar. Both groups were compared with regard to air temperature and air pressure and their occurrence during the year. A regression analysis was performed to identify independent predictors of hypertensive-ICH. Only hypertensive-ICH showed a seasonal pattern and occurred with higher air pressure values and at younger age. Independent predictors of hypertensive-ICH were increased air pressure on the actual day of the event and younger age as well as higher temperature. In the present study with an international cohort, besides age air pressure, more than temperature, had an influence on the occurrence of hypertensive-ICH, only.


Project ECHO Revisited: Propensity Score Analysis And HCV Treatment Outcomes.
Propensity score analysis is a statistical approach to reduce bias often present in non-randomized observational studies. In this paper we use this method to re-analyze data from a study that assessed whether patients receiving HCV treatment from providers in Project ECHO had different clinical outcomes than patients treated by specialists from an academic medical center (UNM HCV clinic) but in which treatment assignment was not randomized. We modeled the best estimated probability of treatment assignment, and then assess differences overall SVR and SVR in patients with genotype 1 infection by treatment arm using Stabilized Inverse Probability of Treatment Weights (SIPTW). Results show that after adjustment for SIPTW, HCV treatment outcomes were significantly better for the ECHO patients compared to the UNM HCV clinic patients. Higher proportions of patients treated by primary care providers achieved SVR and SVR with genotype 1 compared to those treated at UNM HCV clinic with 15.1% and 16.3% absolute differences, respectively. These results indicate that previously published results (showing no differences) were biased, and resulted in an underestimation of the treatment effect of ECHO on HCV treatment.


Serotonin reuptake inhibitors and hyperprolactinaemia: a case/non-case study in the French pharmacovigilance database.
Hyperprolactinaemia is a common endocrinological disorder that can be caused by a variety of physiological and pathological conditions, although in a large proportion of cases hyperprolactinaemia is drug-induced. Serotonin reuptake inhibitors (SRIs) are reportedly associated with hyperprolactinaemia; however, the number of published cases in the literature is limited. The aim of the study was to investigate the association between exposure to SRIs and the risk of reporting of hyperprolactinaemia in a spontaneous reporting database. All cases of adverse drug reactions (ADRs) involving hyperprolactinaemia spontaneously reported to the French Pharmacovigilance Database from 1985 to December 2009 were reviewed. Cases of hyperprolactinaemia in SRI users were described. In a case/non-case analysis, the association between reported cases of hyperprolactinaemia and the use of SRIs was assessed by calculating reporting odds ratios (ROR) with their 95% confidence intervals (CIs). A total of 11 863 reports with SRIs were collected, of which 187 reported hyperprolactinaemia ADRs. Subjects were 39.7 ± 13.5 years of age on average and mainly female (71%). We observed an increased risk of reporting of hyperprolactinaemia with the use of SRIs as antidepressants (overall ROR 3.3; 95% CI 2.8, 3.8), particularly with fluvoxamine (ROR 4.5; 95% CI 2.8, 7.2), citalopram (ROR 3.9; 95% CI 2.6, 5.8), fluoxetine (ROR 3.6; 95% CI 2.8, 4.7) and paroxetine (ROR 3.1; 95% CI 2.3, 4.2). Duloxetine, milnacipran and sertraline were not associated with an increased risk of reporting of hyperprolactinaemia. Treatment with SRIs is associated with an increased risk of reported hyperprolactinaemia. When investigating the aetiology of diagnosed hyperprolactinaemia, physicians should systematically enquire about treatment with SRIs. The risk of hyperprolactinaemia should be mentioned in the labelling of all SRI compounds.


Acute and Chronic Effects of Dietary Lactose in Adult Rats Are not Explained by Residual Intestinal Lactase Activity.
Neonatal rats have a high intestinal lactase activity, which declines around weaning. Yet, the effects of lactose-containing products are often studied in adult animals. This report is on the residual, post-weaning lactase activity and on the short- and long-term effects of lactose exposure in adult rats. Acutely, the postprandial plasma response to increasing doses of lactose was studied, and chronically, the effects of a 30% lactose diet fed from postnatal (PN) Day 15 onwards were evaluated. Intestinal lactase activity, as assessed both in vivo and in vitro, was compared between both test methods and diet groups (lactose vs. control). A 50%-75% decreased digestive capability towards lactose was observed from weaning into adulthood. Instillation of lactose in adult rats showed disproportionally low increases in plasma glucose levels and did not elicit an insulin response. However, gavages comprising maltodextrin gave rise to significant plasma glucose and insulin responses, indicative of a bias of the adult GI tract to digest glucose polymers. Despite the residual intestinal lactase activity shown, a 30% lactose diet was poorly digested by adult rats: the lactose diet rendered the animals less heavy and virtually devoid of body fat, whereas their cecum tripled in size, suggesting an increased bacterial fermentation. The observed acute and chronic effects of lactose exposure in adult rats cannot be explained by the residual intestinal lactase activity assessed.