Clinicopathological characteristic of ciliated muconodular papillary tumour of the lung.
Ciliated muconodular papillary tumour (CMPT) is a rare tumour characterised by tripartite cellular components of mucinous cells, ciliated columnar cells and basal cells with a predominantly papillary architecture. Its clinicopathological characteristics and treatment methods have not been fully elucidated. Twenty-six patients with CMPT diagnosed and treated in our hospital were retrospectively analysed. The cohort was composed of 13 males and 13 females, with a mean age of 64.4±5.93 years. The diameter of the primary tumour ranged from 0.3 to 1.4 cm. The lesions appeared as subsolid nodules, ground-glass nodules and cavitary nodules under the CT scan. All the patients underwent surgical treatment and did not receive postoperative adjuvant therapy. All the CMPTs were diagnosed by immunohistochemistry and not by intraoperative frozen sections. Next-generation sequencing detection demonstrated EGFR, KRAS and BRAF mutations and ALK rearrangements in CMPTs. The follow-up duration ranged from 5 to 65 months, and no case of tumour recurrence was observed until the final follow-up. The incidence of CMPT is low, and the prognosis is good. Immunohistochemistry is helpful for an accurate diagnosis of CMPT, while intraoperative frozen sections cannot fully guide the surgical method. Sublobectomy may be enough without adjuvant treatment. CMPTs exhibited a relatively high rate of driver gene mutations, while the mutation sites were not consistent with those in lung adenocarcinoma.


Ultrasound-guided fine needle aspiration biopsy of thyroid nodules performed in the office.
The majority of thyroid fine needle aspiration biopsies (FNAB) today are performed in the office freehand by palpation. Not infrequently, patients are sent to radiology for an ultrasound-guided FNAB (USG-FNB). Real-time ultrasound (US) allows for continuous visualization of the needle during insertion and sampling. Historically, USG-FNAB has been a procedure performed by a radiologist in a designated radiology suite. In more recent years, with the development of smaller more portable US machines, there has been a push for clinicians other than radiologists to perform the procedure. To evaluate the accuracy and specimen adequacy of thyroid FNAB performed in the office under US guidance by one senior otolaryngologist. Retrospective chart review of 203 patients who underwent ultrasound-guided USG-FNA of the thyroid gland between September, 2005, to February, 2007, in the office setting by one senior otolaryngologist. Specimens were reviewed onsite at the time of biopsy for cellular adequacy by a cytotechnologist. A total of 203 patients, 176 females and 27 males, underwent USG-FNA of the thyroid gland. The average age of the females was 52 years, and 59.4 years for the males. A total of 271 FNA biopsies were performed. Two hundred and twenty FNAB were satisfactory specimens (81.2%), 26 were unsatisfactory (9.6%), and 25 (9.2%) were limited due to blood clotting or hypocellularity. Of the FNA specimens that had enough cells to evaluate, 159 were benign, 48 were indeterminate for malignacy, and 13 were positive for malignancy. Of the nodules biopsied, 143 were greater than 1.5 cm (average 2.59 cm, unsatisfactory rate 12.6%), and 128 were less than 1.5 cm (average 1.21 cm, unsatisfactory rate 6.3%). In 44 patients, one or more nodule was biopsied at the same office visit. Thyroid US is an indispensable tool in the workup and diagnosis of thyroid disease. It may be used to help identify pathology and physical features suspicious for malignancy and guide FNAB of suspicious nodules. The availability of an office US machine allows the referring physician to perform a service that is normally done in a different department. This ultimately frees up time for both the patient and physician and reduces health care costs by eliminating extra office visits. More importantly, it allows the primary physician to be more knowledgeable and hands on with the patient's overall care. This study shows that a trained physician may perform a USG-FNA of the thyroid gland in the office with results comparable to that in the radiology literature.


[Efficacy of neurogenic and humoral stimuli in venous return in cats].
Humoral stimuli (i.v. adrenaline) proved to exert a greater effect on venous return in anesthetized cats than neurogenic those (electrical stimulation of either brain stem or femoral nerve). The part of cardiac output, however, in arterial blood shifts was the same. The latter finding is, probably, due to a discrepancy between changes occurring in the venous return and cardiac output caused by blood detention within the lung circulation as well as by an elevation of the blood pressure.


Chromatin evolution and molecular drive in speciation.
Are there biological generalities that underlie hybrid sterility or inviability? Recently, around a dozen "speciation genes" have been identified mainly in Drosophila, and the biological functions of these genes are revealing molecular generalities. Major cases of hybrid sterility and inviability seem to result from chromatin evolution and molecular drive in speciation. Repetitive satellite DNAs within heterochromatin, especially at centromeres, evolve rapidly through molecular drive mechanisms (both meiotic and centromeric). Chromatin-binding proteins, therefore, must also evolve rapidly to maintain binding capability. As a result, chromatin binding proteins may not be able to interact with chromosomes from another species in a hybrid, causing hybrid sterility and inviability.


A nonlinear regression model as applied to the comparison of axis-angles of electrocardiographic systems.
The systematic nonlinearity exhibited in a comparison of 2 commonly used electrocardiographic lead-systems, when the net QRS axis-angle from one system is plotted against the other, is quantitatively analyzed. A family of nonlinear correlation curves is implemented using the ratio of 2 correction factors, fc/fo, as a parameter. Such curves, replacing linear regression lines, provide a more realistic representation of the actual problem of this type. Between the Frank and the 12-lead systems, the value of fc/fo is found to be 0.53 for the frontal plane from a sample of 1,000 subjects. The combination of correction factors, fc=1.155 and fo=2.18, is a possibility among countless others to make up the same fc/fo of 0.53. Appreciable improvement in axis correlation is demonstrated after the data are corrected by such factors.


[Free radicals and HIV infection].
In HIV infected patients, the increase of the concentration of free radicals is related to: a depletion of protective system (glutathione peroxidase, superoxide dismutase, vitamin E, selenium ...), and an increased production of free radicals (superoxide anion, hydrogen peroxide, hydroxil radical) consecutive to the activation of lymphocytes and phagocyting cells, the chronic inflammation, the increased polyinsatured fatty acids concentration and lipoperoxidation, and direct or indirect effect of several pathologic agents including Mycoplasma sp. This free radical excess could impair cell membranes and generate apoptosis, the main cause of lymphocytes CD4+ depletion. After a brief review of the free radicals synthesis pathway, their potential deleterious effects and the protective systems, the role of free radicals in the pathogenesis of HIV infection are discussed in regard to data reported in the literature.


Decision making after BRCA genetic testing. Down the road of transition.
The purpose of this study was to evaluate women who have completed hereditary cancer risk assessment and BRCA genetic testing to determine if they considered themselves prepared to proceed with decision making regarding cancer screening and prevention options. Levels of decisional conflict were explored, as was their preference for information delivery. The prospective, descriptive survey was conducted at a breast and clinical genetics clinic at a comprehensive cancer center in the northeastern United States. Twenty-seven female participants completed the Preparation for Decision Making scale, Decisional Conflict Scale, and a demographic questionnaire. Scores were consistent with high levels of preparation for decision making and low decisional conflict. The face-to-face approach was the preferred method for information delivery. Subgroup analysis demonstrated a difference in the measured objectives based on cancer status but not based on BRCA status. The current information delivery approach is meeting the decision-making needs of women considered to be at increased risk for hereditary breast and ovarian cancer.


Heterogeneity of monoclonal antibody distribution and radiation dose in tumors: a modeling analysis.
For successful use of monoclonal antibodies and their conjugates for diagnosis and therapy, it is helpful to understand both macroscopic and microscopic aspects of antibody distribution. Antibody distribution in a tumor is simulated by splicing together information on global pharmacokinetics, transport across the capillary wall, diffusive penetration through the tumor interstitial space, and antigen-antibody interaction. One interesting implication of this simulation is a microscopic dosimetry for radioimmunotherapy. The information of microscopic radioconjugate distribution will enable us to calculate absorbed dose in a tumor at the microscopic scale. The first step is to simulate the spatial antibody concentration profile in a tumor as a function of time after intravenous (bolus) injection, using reasonable values for the parameters involved. The second step is to calculate, also as a function of time, the absorbed radiation dose distribution resulting from each concentration profile. Parameter values for IgG pharmacology and a radiation point source function for I-131 are used to explore the effect of affinity on the antibody distribution and consequent absorbed dose in the tumor. The geometry simulated corresponds to a spherical nodule of densely packed tumor cells. Absorbed doses are calculated for radiation from a single nodule and for a cubic lattice of such nodules. This modeling analysis demonstrates that 1) antigen-antibody binding in tumors can retard antibody percolation; 2) high antibody affinity at a given dose tends to decrease antibody percolation and result in a heterogeneous distribution; 3) heterogeneous antibody distribution results in heterogeneous absorbed dose. This is more apparent in the case of radiation from a single nodule or small tumors. PERC and PERC-RAD, the computer program packages developed for these analyses, provide a convenient and flexible way to assess the impact of macroscopic and microscopic parameters on the distribution of immunoconjugates (PERC) and the consequent absorbed radiation dose in tumors (PERC-RAD). This mathematical model and the general principles developed here can be applied as well as to other biological ligands and beta-emitters.


Impact of Fruit and Fruit Juice on Death and Disease Incidence: A Sex-Specific Longitudinal Analysis of 18 603 Adults.
The health benefits of fruits are well established, but fruit juice has been more controversial. Fruit and juice are often ingested with other foods, which prompted our investigation to determine whether fruit consumed as juice may negate the beneficial effects of consuming whole fruit in people with cardiovascular disease. We retrospectively analyzed data from a population-based study in Australia (the 45 and Up Study) linked with hospitalization and mortality data up to September 2018. Kaplan-Meier survival estimates and Cox proportional hazards models were used to examine effects of fruit, fruit juice, and the combination of fruit and fruit juice in relation to death and disease incidence among men and women living with cardiovascular disease. A total of 7308 deaths occurred among 18 603 participants diagnosed with cardiovascular disease over a 13-year follow-up. After multivariable adjustment, inadequate fruit intake (hazard ratio [HR], 1.12 [95% CI, 1.01-1.24]) and high fruit juice intake (HR, 1.26 [95% CI, 1.12-1.41]) predicted all-cause mortality in women. Also, high fruit juice intake plus either adequate fruit intake (HR, 1.18 [95% CI, 1.02-1.37]) or inadequate fruit intake (HR, 1.43 [95% CI, 1.21-1.69]) predicted mortality in women. No relationships were found in men after multivariable adjustments. Also, we found no prognostic value for fruit and fruit juice intake on disease incidence. In adults with cardiovascular disease, we found that fruit juice (in combination with adequate or inadequate fruit intake) predicted mortality in women but not in men. These effects became less clear when focusing on disease incidence.


Effect of Cognitive Training in Fully Immersive Virtual Reality on Visuospatial Function and Frontal-Occipital Functional Connectivity in Predementia: Randomized Controlled Trial.
Cognitive training can potentially prevent cognitive decline. However, the results of recent studies using semi-immersive virtual reality (VR)-assisted cognitive training are inconsistent. We aimed to examine the hypothesis that cognitive training using fully immersive VR, which may facilitate visuospatial processes, could improve visuospatial functioning, comprehensive neuropsychological functioning, psychiatric symptoms, and functional connectivity in the visual brain network in predementia. Participants over 60 years old with subjective cognitive decline or mild cognitive impairment from a memory clinic were randomly allocated to the VR (n=23) or the control (n=18) group. The VR group participants received multidomain and neuropsychologist-assisted cognitive training in a fully immersive VR environment twice a week for 1 month. The control group participants did not undergo any additional intervention except for their usual therapy such as pharmacotherapy. Participants of both groups were evaluated for cognitive function using face-to-face comprehensive neuropsychological tests, including the Rey-Osterrieth Complex Figure Test (RCFT) copy task; for psychiatric symptoms such as depression, apathy, affect, and quality of life; as well as resting-state functional magnetic resonance imaging (rsfMRI) at baseline and after training. Repeated-measures analysis of variance was used to compare the effect of cognitive training between groups. Seed-to-voxel-based analyses were used to identify the cognitive improvement-related functional connectivity in the visual network of the brain. After VR cognitive training, significant improvement was found in the total score (F1,39=14.69, P=.001) and basic components score of the RCFT copy task (F1,39=9.27, P=.005) compared with those of the control group. The VR group also showed improvements, albeit not significant, in naming ability (F1,39=3.55, P=.07), verbal memory delayed recall (F1,39=3.03, P=.09), and phonemic fluency (F1,39=3.08, P=.09). Improvements in psychiatric symptoms such as apathy (F1,39=7.02, P=.01), affect (F1,39=14.40, P=.001 for positive affect; F1,39=4.23, P=.047 for negative affect), and quality of life (F1,39=4.49, P=.04) were found in the VR group compared to the control group. Improvement in the RCFT copy task was associated with a frontal-occipital functional connectivity increase revealed by rsfMRI in the VR group compared to the control group. Fully immersive VR cognitive training had positive effects on the visuospatial function, apathy, affect, quality of life, and increased frontal-occipital functional connectivity in older people in a predementia state. Future trials using VR cognitive training with larger sample sizes and more sophisticated designs over a longer duration may reveal greater improvements in cognition, psychiatric symptoms, and brain functional connectivity. Clinical Research Information Service KCT0005243; https://tinyurl.com/2a4kfasa.


Antibodies in oncology.
Monoclonal antibodies (mAbs) have become one of the largest classes of new therapeutic agents approved for use in oncology, and have revolutionised the treatment of many human malignancies. Clinically useful mAbs can function through several different mechanisms, including inhibition of tumour-related signalling, induction of apoptosis, inhibition of angiogenesis, enhancing host immune response against cancer and targeted delivery of payloads (such as toxins, cytotoxic agents or radioisotopes) to the tumour site. The increasing knowledge of key molecules and cellular pathways involved in tumour induction and progression has led to a rise in the proportion of therapeutic mAbs entering clinical trials. These mAbs consist of various conventional or recombinant, murine, humanised, chimeric or fully human and fusion constructs. In this review, we provide an overview of mAbs approved for use in clinical oncology and those currently in clinical development. We also discuss the mechanisms of action of anti-cancer mAbs, as well as the antigen targets recognised by these antibodies.


Spatial resolution of epicardial pace mapping using body surface potentials.
Body surface potential maps (BSPMs) recorded during pace mapping provide an important non-invasive means for identifying local cardiac events; recent clinical studies demonstrated that endocardial pacing sites can be resolved within less than 10 mm. We sought to determine whether similar spatial resolution could be achieved during epicardial pacing. Four patients who were undergoing either heart valve replacement (one), aortocoronary bypass graft (one), or both (two) were studied. In each patient, a pair of epicardial electrodes was placed intraoperatively at the middle aspect of the right ventricular free wall. The distance between the neighbouring electrodes was 10 mm. Five days after the surgery, ECGs were acquired from 35 leads during pacing from each epicardial electrode. We determined the distributions of QRS integrals (the net area under the ECG signal) and compared integrals corresponding to pacing from each of the adjacent electrodes using statistical indices. Student's t-test was applied to these indices and in all the patients revealed that differences in distributions of QRS integral maps were statistically significant (p < 0.01). Results of our study indicate that the non-invasive acquisition of body surface ECGs could resolve epicardial breakthrough sites within 10 mm, which may be useful in facilitating therapeutic ablations in patients with ventricular tachycardias.


Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylene-covered stent grafts.
The aim of this study was to assess the incidence, natural history, and risk factors of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) with the new polytetrafluoroethylene (PTFE)-covered stent grafts in cirrhotic patients. Seventy-eight cirrhotic patients treated by TIPS with PTFE-covered stent grafts and followed by the same medical team--according to a prospective protocol for diagnostic workup and surveillance strategy--were reviewed. The follow-up was 19.9 +/- 20.6 months. At least one episode of HE occurred in 35 of 78 (44.8%) patients. The probability of remaining free of HE was 53.8% (95% confidence interval [CI] 41.4-66.2] at 1 yr and 50.9% at 2 yr (95% CI 38.2-63.8%). The total number of HE episodes was 89. Fifty-five percent of the episodes were grades III-IV. The occurrence of HE tended to be constant during the follow-up, probably because of the very low incidence of shunt dysfunction (13.6% at 2 yr). Moreover, in six patients, a refractory HE required the reduction of the shunt diameter. One patient died due to variceal bleeding after this procedure. At a multivariate analysis, an older age, high creatinine levels, and low serum sodium and low albumin values were shown to be independent factors for the occurrence of HE. Serum creatinine level was the only variable related to the development of refractory HE at the logistic multivariate analysis. HE after TIPS with PTFE-covered stent grafts is frequent; its incidence is not confined to the first post-TIPS period, but it has the tendency to be frequent over time. Refractory HE occurred in 8% of patients and may be successfully managed by reducing the stent diameter. The selection of patients undergoing TIPS placement should be very accurate, especially for those subjects with abnormal creatinine level.


Deciphering the Role of Filamin B Calponin-Homology Domain in Causing the Larsen Syndrome, Boomerang Dysplasia, and Atelosteogenesis Type I Spectrum Disorders via a Computational Approach.
Filamins (FLN) are a family of actin-binding proteins involved in regulating the cytoskeleton and signaling phenomenon by developing a network with F-actin and FLN-binding partners. The FLN family comprises three conserved isoforms in mammals: FLNA, FLNB, and FLNC. FLNB is a multidomain monomer protein with domains containing an actin-binding N-terminal domain (ABD 1-242), encompassing two calponin-homology domains (assigned CH1 and CH2). Primary variants in FLNB mostly occur in the domain (CH2) and surrounding the hinge-1 region. The four autosomal dominant disorders that are associated with FLNB variants are Larsen syndrome, atelosteogenesis type I (AOI), atelosteogenesis type III (AOIII), and boomerang dysplasia (BD). Despite the intense clustering of FLNB variants contributing to the LS-AO-BD disorders, the genotype-phenotype correlation is still enigmatic. In silico prediction tools and molecular dynamics simulation (MDS) approaches have offered the potential for variant classification and pathogenicity predictions. We retrieved 285 FLNB missense variants from the UniProt, ClinVar, and HGMD databases in the current study. Of these, five and 39 variants were located in the CH1 and CH2 domains, respectively. These variants were subjected to various pathogenicity and stability prediction tools, evolutionary and conservation analyses, and biophysical and physicochemical properties analyses. Molecular dynamics simulation (MDS) was performed on the three candidate variants in the CH2 domain (W148R, F161C, and L171R) that were predicted to be the most pathogenic. The MDS analysis results showed that these three variants are highly compact compared to the native protein, suggesting that they could affect the protein on the structural and functional levels. The computational approach demonstrates the differences between the FLNB mutants and the wild type in a structural and functional context. Our findings expand our knowledge on the genotype-phenotype correlation in FLNB-related LS-AO-BD disorders on the molecular level, which may pave the way for optimizing drug therapy by integrating precision medicine.


DNA-mediated gene transfer: recombination between cotransferred DNA sequences and recovery of recombinants in a plasmid.
Ltk- aprt- mouse L cells were transformed to the tk+ phenotype with 10 ng of the herpes simplex virus-1 thymidine kinase (tk) gene and 20 micrograms of pBR322 or simian virus 40 (SV40) DNA. DNAs from five cloned cell lines show restriction endonuclease fragments that hybridize to both tk and pBR322 or SV40 DNA. In all of the cell lines some of these fragments also contain cellular DNA sequences. The use of carrier DNAs with defined sequences has enabled us to demonstrate that the joining of carrier and selectable gene sequences occurs in mouse cells. In one case we have been able to use the ampicillin resistance marker of pBR322 to "rescue" a recombinant plasmid. An analysis of the junction between pBR322 and tk in this plasmid suggests that a small area of homology (16 of 19 base pairs) might be involved in the recombination process.


The addition of a water flosser to power tooth brushing: effect on bleeding, gingivitis, and plaque.
The primary objective of this study was to compare the effectiveness of a water flosser plus sonic toothbrush to a sonic toothbrush alone on the reduction of bleeding, gingivitis, and plaque. The secondary objective was to compare the effectiveness of different sonic toothbrushes on bleeding, gingivitis, and plaque. One-hundred and thirty-nine subjects completed this randomized, four-week, single-masked, parallel clinical study. Subjects were assigned to one of four groups: Waterpik Complete Care, which is a combination of a water flosser plus power toothbrush (WFS); Sensonic Professional Plus Toothbrush (SPP); Sonicare FlexCare toothbrush (SF); or an Oral-B Indicator manual toothbrush (MT). Subjects were provided written and verbal instructions for all power products at baseline, and instructions were reviewed at the two-week visit. Data were evaluated for whole mouth, facial, and lingual surfaces for bleeding on probing (BOP) and gingivitis (MGI). Plaque data were evaluated for whole mouth, lingual, facial, approximal, and marginal areas of the tooth using the Rustogi Modification of the Navy Plaque Index (RMNPI). Data were recorded at baseline (BL), two weeks (W2), and four weeks (W4). All groups showed a significant reduction from BL in BOP, MGI, and RMNPI for all areas measured at the W2 and W4 visits (p < 0.001). The reduction of BOP was significantly higher for the WFS group than the other three groups at W2 and W4 for all areas measured (p < 0.001 for all, except p = 0.007 at W2 and p = 0.008 for W4 lingual comparison to SPP). The WFS group was 34% more effective than the SPP group, 70% more effective than the SF group, and 1.59 times more effective than the MT group for whole mouth bleeding scores (p < 0.001) at W4. The reduction of MGI was significantly higher for the WFS group; 23% more effective than SPP, 48% more effective than SF, and 1.35 times more effective than MT for whole mouth (p <0.001) at W4. The reduction of MGI was significantly higher for WFS than the SF and MT for facial and lingual surfaces, and more effective than the SPP for facial surfaces (p < 0.001) at W4. The WFS group showed significantly better reductions for plaque than the SF and MT groups for whole mouth, facial, lingual, approximal, and marginal areas at W4 (p < 0.001; SF facial p = 0.025). For plaque reduction, the WFS was significantly better than the SPP for whole mouth (p = 0.003) and comparable for all other areas and surfaces at W4. The WFS was 52% more effective for whole mouth, 31% for facial, 77% for lingual, 1.22 times for approximal, and 1.67 times for marginal areas compared to the SF for reducing plaque scores at W4 (p < 0.001; SF facial p = 0.025). The SPP had significantly higher reductions than the SF for whole mouth and lingual BOP and MGI scores, and whole mouth, approximal, marginal, and lingual areas for plaque at W4. The Waterpik Complete Care is significantly more effective than the Sonicare FlexCare toothbrush for reducing gingival bleeding, gingivitis, and plaque. The Sensonic Professional Plus Toothbrush is significantly more effective than the Sonicare Flex-Care for reducing gingival bleeding, gingivitis, and plaque.


Infantile ovariectomy potentiates the stimulatory effect of oestrogen/progesterone on LH secretion in the rat.
Ovariectomy of prepubertal rats (9 days of age) eliminates the ability of the opiate peptide FK 33-824 to inhibit LH secretion when tested 19 days later. We have investigated whether this removal of opiate inhibition would modify the LH/FSH response to stimulation with oestradiol benzoate/progesterone priming. Ovariectomy of rats during infancy (9 days after birth) amplifies the stimulatory effects of these steroids on LH/FSH secretion when tested 19 days later. This amplification was not seen in rats ovariectomized before (day 24) or after puberty (day 43) and tested 19 days later. The pituitary content of LH/FSH does not appear to contribute to this phenomenon, though increased responsiveness to injected gonadotrophin-releasing hormone (GnRH) is clearly involved; ovariectomy at day 9 is considerably more effective than ovariectomy at day 24 of life in enhancing the response to GnRH. We conclude that infantile ovariectomy either removes, or prevents the development of, a hypothalamic inhibitory mechanism which normally modulates the responsiveness of the pituitary to stimulation with GnRH.


Ideas in pathology. Focal and segmental glomerulosclerosis.
Focal and segmental glomerulosclerosis (FGS) is an important cause of the nephrotic syndrome and renal failure in children and adults. This review will present a detailed description of the pathological and clinical features of FGS and discuss in depth the modern concepts of its pathogenesis, which recent studies indicate is multifactorial and analogous to that of atherosclerosis.


Effects of ozone on activated sludge: performance of anaerobic digestion and structure of the microbial community.
The treatment and disposal of activated sludge are currently challenging tasks in the world. As a common biological engineering technology, biological fermentation exists with disadvantages such as low efficiency and complex process. Ozone pretreatments are commonly applied to improve this problem due to their high efficiency and low cost. In this study, the significant function of ozone in anaerobic fermentation gas production was verified with excess sludge. Compared with other untreated sludge, ozone pretreatment can effectively degrade activated sludge. After ozone treatment and mixing with primary sludge, the methane production of excess sludge increased by 49.30 and 50.78%, and the methanogenic activity increased by 69.99 and 73.83%, respectively. The results indicated that the mixing of primary sludge with excess sludge possessed synergistic effects, which contributed to the anaerobic fermentation of excess sludge. The results of microbial community structure exhibited that methanogenic processes mainly involve hydrogenogens, acidogens and methanogens. The relative abundance of both bacteria and microorganisms changed significantly in the early stage of hydraulic retention time, which coincided exactly with the gas production stage. This study provided a feasible pretreatment strategy to improve sludge biodegradability and revealed the role of microorganisms during anaerobic digestion.


Cassia Angustifolia Primed ASCs Accelerate Burn Wound Healing by Modulation of Inflammatory Response.
Thermal traumas impose a huge burden on healthcare systems. This merits the need for advanced but cost-effective remedies with clinical prospects. In this context, we prepared a regenerative 3D-construct comprising of Cassia angustifolia extract (SM) primed adipose-derived stem cells (ASCs) laden amniotic membrane for faster burn wound repair. ASCs were preconditioned with SM (30 µg/ml for 24 h), and subsequently exposed to in-vitro thermal injury (51 °C,10 min). In-vivo thermal injury was induced by placing pre-heated copper-disc (2 cm diameter) on dorsum of the Wistar rats. ASCs (2.0 × 105) pre-treated with SM (SM-ASCs), cultured on stromal side of amniotic membrane (AM) were transplanted in rat heat-injury model. Non-transplanted heat-injured rats and non-heat-injured rats were kept as controls. The significantly upregulated expression of IGF1, SDF1A, TGFβ1, VEGF, GSS, GSR, IL4, BCL2 genes and downregulation of BAX, IL6, TNFα, and NFkB1 in SM-ASCs in in-vitro and in-vivo settings confirmed its potential in promoting cell-proliferation, migration, angiogenesis, antioxidant, cell-survival, anti-inflammatory, and wound healing activity. Moreover, SM-ASCs induced early wound closure, better architecture, normal epidermal thickness, orderly-arranged collagen fibers, and well-developed skin appendages in healed rat-skin transplanted with AM+SM-ASCs, additionally confirmed by increased expression of structural genes (Krt1, Krt8, Krt19, Desmin, Vimentin, α-Sma) in comparison to untreated-ASCs laden-AM transplanted in heat injured rats. SM priming effectively enabled ASCs to counter thermal injury by significantly enhancing cell survival and reducing inflammation upon transplantation. This study provides bases for development of effective combinational therapies (natural scaffold, medicine, and stem cells) with clinical prospects for treating burn wounds.


[Optic neuropathy and Parry-Romberg syndrome. Apropos of a case].
The present paper reports on the case of a 44 year-old woman with progressive facial hemiatrophy associated with bilateral papillitis who developed an acquired complete third nerve palsy on the unaffected side six months later. This Romberg's disease occurred in the context of an immunologic disturbance which was barely improved by steroids and Disulone. Ophthalmic involvement, particularly neurologic involvement, pathogenic hypothesis are reviewed. The responsibility of sympathetic disorder in Parry-Romberg disease is based on frequent association of progressive facial hemiatrophy and Fuch's and Horner's syndromes.


Technology assessment, soviet style.
The Soviet Union is actively considering two plans to divert large northern lakes and rivers to the south of the country. If adopted, these would rank among the most expensive and complicated engineering projects ever undertaken, with unforeseeable but possibly far-reaching environmental effects. The plans, now at an advanced stage, have aroused a spirited public controversy, providing an unusual glimpse of Soviet policy-making and technology assessment. Major decisions are due by 1985. The question is, what will happen to the quality and openness of this debate as the political stakes rise and the time of decision draws near?


The Effect of Acepromazine Maleate on Feeder Steers in Transit and Feedlot.
The tranquilizer, acepromazine maleate, was evaluated using 34 yearling Hereford feeder steers. Animals injected prior to loading lost significantly less weight (29.5%) during transit from Edmonton to Winnipeg than their untreated counterparts. The weight loss difference following arrival at Macdonald College, Quebec, was not significant. During a short term feeding period the group fed ace promazine maleate gained significantly more rapidly (12.8%) than the control group. There were no significant differences in dressing percentage or carcass grade.


A randomized study of paclitaxel versus cyclophosphamide/methotrexate/5-fluorouracil/prednisone in previously untreated patients with advanced breast cancer: preliminary results. Taxol Investigational Trials Group, Australia/New Zealand.
When administered as a single agent to previously treated patients with advanced breast cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has good activity. This trial was undertaken to compare paclitaxel with standard chemotherapy as front-line treatment for this disease. Patients with measurable or evaluable metastatic breast cancer, no prior chemotherapy for metastatic disease, and Eastern Cooperative Oncology Group performance status of 0 to 2 were randomized to receive either paclitaxel 200 mg/m2 intravenously over 3 hours for eight cycles over 24 weeks or standard treatment with oral cyclophosphamide 100 mg/m2/d days 1 to 14, intravenous methotrexate 40 mg/m2 days 1 and 8, intravenous 5-fluorouracil 600 mg/m2 days 1 and 8, and oral prednisone 40 mg/m2 daily days 1 to 14 (CMFP) for six cycles over 24 weeks. Patients whose disease progressed or relapsed were recommended for second-line therapy with epirubicin. Accrual has been completed with 209 patients randomized, and an interim analysis of the first 100 patients is reported here. Analysis of quality of life, assessed by the linear analogue scale and overall quality of life indices, is ongoing. Objective response occurred in 31% (confidence interval, 19% to 45%) with paclitaxel and 35% (confidence interval, 22% to 51%) with CMFP, with stable disease in an additional 33% and 29%, respectively. Median time to progression was 5.5 months with paclitaxel and 6.4 months with CMFP, with a median survival of 17.3 months for patients treated with paclitaxel and 11.3 months for those given CMFP. Grades 3 and 4 neutropenia occurred in 64% of patients with paclitaxel and 63% with CMFP. However, febrile neutropenia was the primary reason for hospitalization in 1% of paclitaxel courses, compared with 8% with CMFP. Major infections (World Health Organization grade 4) were seen in 7% of patients treated with CMFP, but in none of those given paclitaxel. Moderate or severe mucositis occurred in 13% of paclitaxel and 27% of CMFP patients. Alopecia and peripheral neuropathy were more common with paclitaxel. Quality of life assessments in the first 100 patients suggest better overall results for those treated with paclitaxel compared with CMFP. Preliminary analyses suggest that single-agent paclitaxel is well tolerated and provides control of metastatic cancer comparable to that of CMFP combination therapy when used as front-line therapy in an outpatient setting.


Rapid remodeling of tight junctions during paracellular diapedesis in a human model of the blood-brain barrier.
Leukocyte transendothelial migration (TEM; diapedesis) is a critical event in immune surveillance and inflammation. Most TEM occurs at endothelial cell borders (paracellular). However, there is indirect evidence to suggest that, at the tight junctions of the blood-brain barrier (BBB), leukocytes migrate directly through the endothelial cell body (transcellular). Why leukocytes migrate through the endothelial cell body rather than the cell borders is unknown. To test the hypothesis that the tightness of endothelial cell junctions influences the pathway of diapedesis, we developed an in vitro model of the BBB that possessed 10-fold higher electrical resistance than standard culture conditions and strongly expressed the BBB tight junction proteins claudin-5 and claudin-3. We found that paracellular TEM was still the predominant pathway (≥98%) and TEM was dependent on PECAM-1 and CD99. We show that endothelial tight junctions expressing claudin-5 are dynamic and undergo rapid remodeling during TEM. Membrane from the endothelial lateral border recycling compartment is mobilized to the exact site of tight junction remodeling. This preserves the endothelial barrier by sealing the intercellular gaps with membrane and engaging the migrating leukocyte with unligated adhesion molecules (PECAM-1 and CD99) as it crosses the cell border. These findings provide new insights into leukocyte-endothelial interactions at the BBB and suggest that tight junctions are more dynamic than previously appreciated.


Effect of high energy electron irradiation on the electromechanical properties of poly (vinylidene fluoride-trifluorethylene) 50/50 and 65/35 copolymers.
High energy electron irradiation with a broad range dosage was carried out on poly(vinylidene fluoride trifluorethylene) copolymer 65/35 mol% and 50/50 mol% films at different temperatures from room temperature to a temperature close to the melt temperature. The effect of irradiation on the properties of the films, such as electric field-induced strain, dielectric and polarisation behaviors, and mechanical modulus, is presented. The irradiated films can exhibit a very large electric field-induced strain, more than 4.5% longitudinal strain, and 3% transverse strain. The transverse strain of the stretched film can compare with the longitudinal strain; that of the unstretched film is much smaller than the longitudinal strain. With regard to the dielectric and polarization behaviors, we found that irradiation changes the copolymer from a typical ferroelectric to a relaxor ferroelectric in which the behavior of microregions under the electric field plays the key role. Between the two copolymers studied, we found that the 65/35 copolymer is preferred for both longitudinal and transverse strain generation. A model is proposed to explain the experimental results that the amplitude of the charge electrostrictive coefficient (Q) increases with decreasing crystallinity.


Treatment Patterns, Complications, and Health Care Utilization Among Endometriosis Patients Undergoing a Laparoscopy or a Hysterectomy: A Retrospective Claims Analysis.
Hysterectomy and laparoscopy are common surgical procedures used for the treatment of endometriosis. This study compares outcomes for women who received either procedure within the first year post initial surgery. The study used data from the Truven Health MarketScan claims databases from 2004 to 2013 to identify women aged 18-49 years who received an endometriosis-related laparoscopy or hysterectomy. Patients were excluded if they did not have continuous insurance coverage from 1 year before through 1 year after their endometriosis-related procedure, if they were diagnosed with uterine fibroids prior to or on the date of surgery (i.e., index date), or if they had a hysterectomy prior to the index date. The descriptive analyses examined differences between patients with an endometriosis-related laparoscopy or hysterectomy in regard to medications prescribed, complications, and hospitalizations during the immediate year post procedure. The final sample consisted of 24,915 women who underwent a hysterectomy and 37,308 who underwent a laparoscopy. Results revealed significant differences between the cohorts, with women who received a laparoscopy more likely to be prescribed a GnRH agonist, progestin, danazol, or an opioid analgesic in the immediate year post procedure compared to women who underwent a hysterectomy. In contrast, women who underwent a hysterectomy generally had higher complication rates. Index hospitalization rates and length of stay (LOS) were higher for women who had a hysterectomy, while post-index hospitalization rates and LOS were higher for women who had a laparoscopy. For both cohorts, post-procedure complications were associated with significantly higher hospitalization rates and longer LOS. This study indicated significantly different 1-year post-surgical outcomes for patients who underwent an endometriosis-related hysterectomy relative to a laparoscopy. Furthermore, the endometriosis patients in this analysis had a considerable risk of surgical complications, subsequent surgeries, and hospital admissions, both during and after their initial therapeutic laparoscopy or hysterectomy. AbbVie.


Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management.
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the motor system in adults that occurs in sporadic, familial, and Western Pacific forms. Involvement of non-motor pathways has been increasingly recognized, both clinically and pathologically. Although the usual course is relentlessly progressive with death in half the cases within three years from onset, it can sometimes be protracted. Degeneration and loss of large motor neurons in the cerebral cortex, brainstem, and cervical and lumbar spinal cord are characteristic. Marked reduction in the number of large myelinated fibers is notable in the cervical and lumbar ventral roots. Peripheral nerves show reduced numbers of large myelinated fibers, acute axonal degeneration at all levels, and distal axonal atrophy. Motor end-plates reveal small or absent nerve terminals. Subclinical non-motor system involvement includes neuronal loss in Clarke's nucleus and dorsal root ganglia, degeneration of non-motor tracts in the spinal cord, loss of receptors in the dorsal horns of the spinal cord, and myelinated fiber loss with segmental demyelination in sensory and mixed nerves. The serious implications of the diagnosis of ALS make it mandatory to exclude similar potentially treatable disorders. Management should be multidisciplinary, and discussions with the patient and family members should be frank and frequent. Discussions about ventilatory support should take place early in the disease so that death from respiratory failure can be prevented, when that is desired, and conversely to obviate the discontent and anger that accompany involuntary life on a ventilator.


Correction of muscular dystrophies by CRISPR gene editing.
Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.


Differential cellular localization of antioxidant enzymes in the trigeminal ganglion.
Because of its high oxygen demands, neural tissue is predisposed to oxidative stress. Here, our aim was to clarify the cellular localization of antioxidant enzymes in the trigeminal ganglion. We found that the transcriptional factor Sox10 is localized exclusively in satellite glial cells (SGCs) in the adult trigeminal ganglion. The use of transgenic mice that express the fluorescent protein Venus under the Sox10 promoter enabled us to distinguish between neurons and SGCs. Although both superoxide dismutases 1 and 2 were present in the neurons, only superoxide dismutase 1 was identified in SGCs. The enzymes relevant to hydrogen peroxide degradation displayed differential cellular localization, such that neurons were endowed with glutathione peroxidase 1 and thioredoxin 2, and catalase and thioredoxin 2 were present in SGCs. Our immunohistochemical finding showed that only SGCs were labeled by the oxidative damage marker 8-hydroxy-2'-deoxyguanosine, which indicates that the antioxidant systems of SGCs were less potent. The transient receptor potential vanilloid subfamily member 1 (TRPV1), the capsaicin receptor, is implicated in inflammatory hyperalgesia, and we demonstrated that topical capsaicin application causes short-lasting mechanical hyperalgesia in the face. Our cell-based assay revealed that TRPV1 agonist stimulation in the presence of TRPV1 overexpression caused reactive oxygen species-mediated caspase-3 activation. Moreover, capsaicin induced the cellular demise of primary TRPV1-positive trigeminal ganglion neurons in a dose-dependent manner, and this effect was inhibited by a free radical scavenger and a pancaspase inhibitor. This study delineates the localization of antioxidative stress-related enzymes in the trigeminal ganglion and reveals the importance of the pivotal role of reactive oxygen species in the TRPV1-mediated caspase-dependent cell death of trigeminal ganglion neurons. Therapeutic measures for antioxidative stress should be taken to prevent damage to trigeminal primary sensory neurons in inflammatory pain disorders.


An unusual intrinsically disordered protein from the model legume Lotus japonicus stabilizes proteins in vitro.
Intrinsic structural disorder is a prevalent feature of proteins with chaperone activity. Using a complementary set of techniques, we have structurally characterized LjIDP1 (intrinsically disordered protein 1) from the model legume Lotus japonicus, and our results provide the first structural characterization of a member of the Lea5 protein family (PF03242). Contrary to in silico predictions, we show that LjIDP1 is intrinsically disordered and probably exists as an ensemble of conformations with limited residual beta-sheet, turn/loop, and polyproline II secondary structure. Furthermore, we show that LjIDP1 has an inherent propensity to undergo a large conformational shift, adopting a largely alpha-helical structure when it is dehydrated and in the presence of different detergents and alcohols. This is consistent with an overrepresentation of order-promoting residues in LjIDP1 compared with the average of intrinsically disordered proteins. In line with functioning as a chaperone, we show that LjIDP1 effectively prevents inactivation of two model enzymes under conditions that promote protein misfolding and aggregation. The LjIdp1 gene is expressed in all L. japonicus tissues tested. A higher expression level was found in the root tip proximal zone, in roots inoculated with compatible endosymbiotic M. loti, and in functional nitrogen-fixing root nodules. We suggest that the ability of LjIDP1 to prevent protein misfolding and aggregation may play a significant role in tissues, such as symbiotic root nodules, which are characterized by high metabolic activity.


Clinafloxacin for Treatment of Burkholderia cenocepacia Infection in a Cystic Fibrosis Patient.
Respiratory infection with Burkholderia cenocepacia is associated with accelerated decline in lung function and increased mortality in cystic fibrosis (CF) patients (A. M. Jones, M. E. Dodd, J. R. W. Govan, V. Barcus, C. J. Doherty, J. Morris, and A. K. Webb, Thorax 59:948-951, 2004, http://dx.doi.org/10.1136/thx.2003.017210). B. cenocepacia often possesses innate resistance to multiple antimicrobial classes, making eradication uncommon in established infection (P. B. Davis, Am J Respir Crit Care Med 173:475-482, 2006, http://dx.doi.org/10.1164/rccm.200505-840OE). We report the use of clinafloxacin in a CF patient with advanced B. cenocepacia infection, present pharmacokinetic (PK) data, and discuss the potential therapeutic role of clinafloxacin in patients with this condition.


Modular Strategy To Expand the Chemical Diversity of DNA and Sequence-Controlled Polymers.
Sequence-defined polymers with customizable sequences, monodispersity, substantial length, and large chemical diversity are of great interest to mimic the efficiency and selectivity of biopolymers. We report an efficient, facile, and scalable synthetic route to introduce many chemical functionalities, such as amino acids and sugars in nucleic acids and sequence-controlled oligophosphodiesters. Through achiral tertiary amine molecules that are perfectly compatible with automated DNA synthesis, readily available amines or azides can be turned into phosphoramidites in two steps only. Individual attachment yields on nucleic acids and artificial oligophosphodiesters using automated solid-phase synthesis (SPS) were >90% in almost all cases. Using this method, multiple water-soluble sequence-defined oligomers bearing a range of functional groups in precise sequences could be synthesized and purified in high yields. The method described herein significantly expands the library of available functionalities for nucleic acids and sequence-controlled polymers.


[Principles of phototherapy and its use in cancer patients].
Phototherapy (PHOT) is a therapeutic option whose effectiveness is determined by its capability to destroy cells, with the benefit of discrimination between healthy and diseased tissue. It is based on the previous administration of a drug acting as a photosensitizing agent, and subsequent laser radiation, which brings about cellular destruction. The objective of this study is to review the principles and methods on which this therapeutic modality is based, as well as its use in the cancer field. To this end, we reviewed the MEDLINE database from 2000 to March 2003. Results show a limited effectiveness in small-sized tumours alone, and as a palliative measure, rather than as a healing therapy.


Factors predicting response to splenectomy in adult patients with idiopathic thrombocytopenic purpura.
Splenectomy is the treatment of choice in the majority of patients affected by idiopathic thrombocytopenic purpura refractory to corticosteroid therapy, but it is not free from early and late complications. As the available literature does not seem to contain any precise indications concerning possible factors predicting the response to splenectomy, the aim of this retrospective study of 65 splenectomized patients was to attempt to identify potentially predictive clinical or laboratory parameters. For the purposes of statistical analysis, the patients were divided into two groups: the first included those with a complete (platelets > 100x10(9)/L) or partial response (platelets 50-100 x10(9)/L) to splenectomy; the second, the non-responders (platelets < 50x10(9)/L). The non-parametric tests were based on the Kruskal-Wallis method for independent samples, and the independent samples were compared using the Chi-square test according to Pearson. Univariate analysis did not reveal any significant correlation between successful splenectomy and age, sex, platelet count at diagnosis, anti-platelets antibody positivity, the site of platelet sequestration, the time between diagnosis and surgery, or the response to high intravenous immunoglobulin doses. However, the probability of success was greater in the patients with a complete or partial pre-operative response to steroid therapy (p<0.05). The factor most frequently associated with the success of splenectomy is the site of autologous platelet sequestration. Our study did not identify any clinical or laboratory parameter clearly predictive of post-splenectomy cure other than a transient response to steroid treatment. This finding needs further confirmation in larger patient populations.


Fine epitope mapping of monoclonal antibody 5F1 reveals anticatalytic activity toward the N domain of human angiotensin-converting enzyme.
Angiotensin I-converting enzyme (ACE, peptidyl dipeptidase, EC 126.96.36.199) is a key enzyme in cardiovascular pathophysiology. A wide spectrum of monoclonal antibodies to different epitopes on the N and C domains of human ACE has been used to study different aspects of ACE biology. In this study we characterized the monoclonal antibody (mAb) 5F1, developed against the N domain of human ACE, which recognizes both the catalytically active and the denatured forms of ACE. The epitope for mAb 5F1 was defined using species cross-reactivity, synthetic peptide (PepScan technology) and phage display library screening, Western blotting, site-directed mutagenesis, and protein modeling. The epitope for mAb 5F1 shows no overlap with the epitopes of seven other mAbs to the N domain described previously and is localized on the other side of the N domain globule. The binding of mAb 5F1 to ACE is carbohydrate-dependent and increased significantly as a result of altered glycosylation after treatment with alpha-glucosidase-1 inhibitor, N-butyldeoxynojirimycin (NB-DNJ), or neuraminidase. Out of 17 species tested, mAb 5F1 showed strict primate ACE specificity. In addition, mAb 5F1 recognized human ACE in Western blots and on paraffin-embedded sections. The sequential part of the epitope for mAb 5F1 is created by the N-terminal part of the N domain, between residues 1 and 141. A conformational region of the epitope was also identified, including the residues around the glycan attached to Asn117, which explains the sensitivity to changes in glycosylation state, and another stretch localized around the motif 454TPPSRYN460. Site-directed mutagensis and inhibition assays revealed that mAb 5F1 inhibits ACE activity at high concentrations due to binding of residues on both sides of the active site cleft, thus supporting a hinge-bending mechanism for substrate binding of ACE.


Comparison of Mast Burkholderia Cepacia, Ashdown + Gentamicin, and Burkholderia Pseudomallei Selective Agar for the Selective Growth of Burkholderia Spp.
Reliable identification of pathogenic Burkholderia spp. like Burkholderia mallei and Burkholderia pseudomallei in clinical samples is desirable. Three different selective media were assessed for reliability and selectivity with various Burkholderia spp. and nontarget organisms. Mast Burkholderia cepacia agar, Ashdown + gentamicin agar, and B. pseudomallei selective agar were compared. A panel of 116 reference strains and well-characterized clinical isolates, comprising 30 B. pseudomallei, 20 B. mallei, 18 other Burkholderia spp., and 48 nontarget organisms, was used for this assessment. While all B. pseudomallei strains grew on all three tested selective agars, the other Burkholderia spp. showed a diverse growth pattern. Nontarget organisms, i.e., nonfermentative rod-shaped bacteria, other species, and yeasts, grew on all selective agars. Colony morphology did not allow unambiguous discrimination. While the assessed selective media reliably allowed the growth of a wide range of B. pseudomallei strains, growth of other Burkholderia spp. is only partially ensured. Growth of various nontarget organisms has to be considered. Therefore, the assessed media can only be used in combination with other confirmative tests in the diagnostic procedure for the screening for melioidosis or glanders.


The suitability of matrix assisted laser desorption/ionization time of flight mass spectrometry in a laboratory developed test using cystic fibrosis carrier screening as a model.
We designed a laboratory developed test (LDT) by using an open platform for mutation/polymorphism detection. Using a 108-member (mutation plus variant) cystic fibrosis carrier screening panel as a model, we completed the last phase of LDT validation by using matrix-assisted laser desorption/ionization time of flight mass spectrometry. Panel customization was accomplished via specific amplification primer and extension probe design. Amplified genomic DNA was subjected to allele specific, single base extension endpoint analysis by mass spectrometry for inspection of the cystic fibrosis transmembrane regulator gene (NM_000492.3). The panel of mutations and variants was tested against 386 blinded samples supplied by "authority" laboratories highly experienced in cystic fibrosis transmembrane regulator genotyping; >98% concordance was observed. All discrepant and discordant results were resolved satisfactorily. Taken together, these results describe the concluding portion of the LDT validation process and the use of mass spectrometry to detect a large number of complex reactions within a single run as well as its suitability as a platform appropriate for interrogation of scores to hundreds of targets.


Diplomate of the National Board: inefficient parallel education.
The National Board of Examinations conducts the Diplomate of the National Board in broad specialities as well as in core super specialities. The programme was meant to provide a common standard and a mechanism of evaluation the These programmes, as per the prospectus of the DNB course are meant to provide the basic level ofcompetence required for the postgraduate qualification in that subject. However, it has failed to meet these objectives. It is imperative to re-examine and revamp the system to improve its credibility and acceptability at both the national and international levels.


Characterization of L-glutamic acid60-L-alanine30-L-tyrosine10-specific suppressor T cells in responder mice restricted by Igh-C-linked genes.
A Ts cell subset has been identified in the spleens of responder mice 3 to 6 wk after immunization with an optimally immunogenic dose of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT). These Ts were positively selected by panning procedures by using a mAb (1248 A4.10) produced by immunization of rats with semipurified mouse GAT-specific, single polypeptide chain suppressor factor. These Ts cells inhibited the activity of virgin Th cells but not memory Th cells and this activity was genetically restricted by genes which are linked to the Ig H chain (Igh) locus on chromosome 12. Use of the Igh recombination strain, BAB.14, which has a crossover near the VHCH region junction, demonstrated that the genes regulating the Igh restriction map telomeric to the VH genes. The Igh-linked restriction regulated the interaction of A4.10+ Ts cells with virgin T cells and not B cells. However, A4.10+ Ts did not act directly on Lyt-2-Th cells, but required the presence of Lyt-2+ cells for suppression. Suppression by GAT-primed A4.10+-Ts cells also required syngenicity at Igh-linked genes by both Lyt-2- and Lyt-2+ T cells. These results indicated that A4.10+-Ts cells were inducer Ts cells which activated Lyt-2+ effector Ts cells which prevented primary GAT specific Th cell activity. The interaction between A4.10+-Ts inducer and effector Ts cells and/or the interaction of the effector Ts and its target cell were restricted by genes linked to the Igh constant region.


Efficacy of Routinely used Analgesics in Management of Pulpal Pain Postoperatively a Clinical Study.
The aim of this study was to evaluate the efficacy of various routinely used analgesics in the management of pulpal pain preoperatively. A total of 150 patients were randomly selected and divided into five groups each. At initial visit, a self-administered questionnaire was given, and patients were asked to mark on the Visual Analog Scale (VAS) indicating severity of pain at that moment which is taken as a pretreatment VAS score. Group I patients received aceclofenac + paracetamol, Group II: ketorolac tromethamine, Group III: lornoxicam + paracetamol, Group IV: tramadol + paracetamol, and Group V: paracetamol. All the patients are requested to record their pain levels at 4 h, 6 h, 8 h, 24 h, and 48 h by means of VAS scores before and after treatment. There was no significant decrease in frequency of pain when compared in the first three groups, whereas in Group III and Group IV, the patients experienced an effective reduction in pain because of sustained releasing ability of these drugs. Overall, there was no statistically significant differences among all the groups. This study suggests that there was no significant difference in reduction of pain preoperatively. However, lornoxicam + paracetamol and tramadol + paracetamol were effective because of their sustained releasing ability. Ketorolac was effective to reduce the pain for shorter duration. Paracetamol can be advised in compromised patients where safety is concerned.


[Colonoscopy - indications and utility].
On the basis of own experiences in 600 examinations and 113 polypectomies a survey is given on indications, contraindications, evidence, therapeutic possibilities and complications of the coloscopy. 38.4% of the patients were referred to coloscopy on account of suspicion of presence of a tumor of the colon, 24.5% on account of a supposed inflammation of the large intestine, 19.2% on account of unclear rectal haemorrhage and 12.1% on account of radiologically diagnosed polyps. In 4.1% of the patients the cases in question were after examinations after coloscopic polypectomy and in 1.8% the cases in question were control examinations after operation of the intestine on account of carcinoma of the colon. The suspicion of tumour was coloscopically confirmed only in 18.1% of the patients who were examined on account of this indication, a supposed inflammation of the large intestine in 29.7%. A source of haemorrhage was proved in 64.8% of the patients who were examined under this question. The after examination of the polypectomized patients resulted in a new proof of polyps in 50%.


δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions.
The ability of neurons to maintain spine architecture and modulate it in response to synaptic activity is a crucial component of the cellular machinery that underlies information storage in pyramidal neurons of the hippocampus. Here we show a critical role for δ-catenin, a component of the cadherin-catenin cell adhesion complex, in regulating spine head width and length in pyramidal neurons of the hippocampus. The loss of Ctnnd2, the gene encoding δ-catenin, has been associated with the intellectual disability observed in the cri du chat syndrome, suggesting that the functional roles of δ-catenin are vital for neuronal integrity and higher order functions. We demonstrate that loss of δ-catenin in a mouse model or knockdown of δ-catenin in pyramidal neurons compromises spine head width and length, without altering spine dynamics. This is accompanied by a reduction in the levels of synaptic N-cadherin. The ability of δ-catenin to modulate spine architecture is critically dependent on its ability to interact with cadherin and PDZ domain-containing proteins. We propose that loss of δ-catenin during development perturbs synaptic architecture leading to developmental aberrations in neural circuit formation that contribute to the learning disabilities in a mouse model and humans with cri du chat syndrome.


An analysis of early developmental trauma in social anxiety disorder and posttraumatic stress disorder.
The early contributions of childhood trauma (emotional, physical, sexual, and general) have been hypothesized to play a significant role in the development of anxiety disorders, such as posttraumatic stress disorder (PTSD) and social anxiety disorder (SAD). The aim of this study was to assess childhood trauma differences between PTSD and SAD patients and healthy controls, as measured by the Early Trauma Inventory. We examined individuals (N = 109) with SAD with moderate/severe early developmental trauma (EDT) (n = 32), individuals with SAD with low/no EDT (n = 29), individuals with PTSD with EDT (n = 17), and healthy controls (n = 31). The mean age was 34 years (SD = 11). Subjects were screened with the Mini-International Neuropsychiatric Interview (MINI), Liebowitz Social Anxiety Scale (LSAS), Clinician-Administered PTSD Scale (CAPS), and Childhood Trauma Questionnaire (CTQ). Analysis of variance was performed to assess group differences. Correlations were calculated between childhood traumas. Although not statistically significant, individuals with PTSD endorsed more physical and sexual childhood trauma compared with individuals with SAD with moderate/severe EDT who endorsed more emotional trauma. For all groups, physical and emotional abuse occurred between ages 6 and 11, while the occurrence of sexual abuse in individuals with PTSD was at 6-11 years and later (13-18 years) in individuals with SAD with moderate/severe EDT. For emotional abuse in all groups, the perpetrator was mostly a primary female caregiver; for sexual abuse, it was mostly a nonfamilial adult male, while for physical abuse, it was mostly a caregiver (male in PTSD and female in SAD with moderate/severe EDT). The contribution of childhood abuse to the development of PTSD and SAD and the differences between these groups and other anxiety disorders should not be ignored and attention should be given to the frequency and severity of these events. The relationship of the perpetrator(s) and the age of onset of childhood abuse are also important considerations as they provide a useful starting point to assess impact over the life course. This can, in turn, guide clinicians on the optimal timing for the delivery of interventions for the prevention of PTSD and SAD.


Colonic perforation in corticosteroid-treated dogs.
Clinical findings for 5 new cases of colonic perforation in corticosteroid-treated dogs were presented and 8 other cases from the literature were reviewed. Colonic perforation was a fatal complication in all 13 dogs, 12 of which had had recent major surgery. Ten dogs were neurosurgical patients, 1 dog received medical therapy for head trauma and nonambulatory paresis, and 2 dogs were operated on for non-neurologic conditions. Dexamethasone was the most frequently used corticosteroid, and 12 dogs received a mean cumulative dose of 6.4 mg/kg over an average period of 5.1 days. Depression, anorexia, and emesis, the most frequent signs attending colonic perforation, became evident 3 to 8 days after surgery. Signs preceded death by an average of 22.3 hours. Correct antemortem diagnosis (5 dogs) and surgical intervention (3 dogs) had no effect on eventual outcome (mortality = 100%). Colonic perforation most frequently developed in the proximal descending portion and always involved the antimesenteric border. Gross fecal contamination of the peritoneal cavity and acute generalized peritonitis were evident in all but one dog. Adhesions were observed at the lesion site in 6 dogs, but prevented gross soilage in only one dog.


Investigation on the accumulation of background and pregnancy outcome information on cases consulted by the Japan Drug Information Institute in Pregnancy.
Since pregnant women are excluded from clinical trials, it is essential to accumulate post-marketing information to evaluate the effects on the fetus of medication use during pregnancy. The Japan Drug Information Institute in Pregnancy (JDIIP) was established at the National Center for Child Health and Development as a Ministry of Health, Labour, and Welfare project to provide patients with information and conduct follow-up surveys. In this study, we investigated the status of the accumulation of JDIIP consultation cases to identify issues for enhancing clinical information appropriate for use during pregnancy and to examine how information should be collected and provided. In addition, the status of descriptions of Japanese package inserts, which are representative of those used by healthcare professionals as a source of information, was confirmed for medications used by JDIIP consultation cases. The characteristics of the JDIIP consultation cases information were that the contents that needed to be adjusted when evaluating the effects on the fetus of medication use during pregnancy were obtained. In addition, the follow-up rate was 83.1%. However, although the number of consultation facilities has increased, the number of consultations has not, indicating the need to further increase the number. It was found that there is limited information on epidemiological studies of clinical use in Japanese package inserts. To improve clinical information on the appropriate use of medications during pregnancy, it is necessary to accumulate more information in the future, and it is considered necessary to consider new approaches utilizing the JDIIP system.


Diterpenoids from the Brown Alga Rugulopteryx okamurae and Their Anti-Inflammatory Activity.
Brown algae of the Family Dictyotaceae produce an array of structurally diverse terpenoids, whose biomedical potential in the anti-inflammatory area has been scarcely explored. Herein, the chemical study of the alga Rugulopteryx okamurae has led to the isolation of ten new diterpenoids: rugukadiol A (1), rugukamurals A-C (2-4), and ruguloptones A-F (6-10). The structures of the new compounds were established by spectroscopic means. Compound 1 exhibits an unprecedented diterpenoid skeleton featuring a bridged tricyclic undecane system. Compounds 2-10 belong to the secospatane class of diterpenoids and differ by the oxygenated functions that they contain. In anti-inflammatory assays, the new diterpenoid 1 and the secospatanes 5 and 10 significantly inhibited the production of the inflammatory mediator NO in LPS-stimulated microglial cells Bv.2 and macrophage cells RAW 264.7. Moreover, compounds 1 and 5 were found to strongly inhibit the expression of Nos2 and the pro-inflammatory cytokine Il1b in both immune cell lines.


Hierarchical modeling of sequential behavioral data: an empirical Bayesian approach.
The authors review the common methods for measuring strength of contingency between 2 behaviors in a behavioral sequence, the binomial z score and the adjusted cell residual, and point out a number of limitations of these approaches. They present a new approach using log odds ratios and empirical Bayes estimation in the context of hierarchical modeling, an approach not constrained by these limitations. A series of hierarchical models is presented to test the stationarity of behavioral sequences, the homogeneity of sequences across a sample of episodes, and whether covariates can account for variation in sequences across the sample. These models are applied to observational data taken from a study of the behavioral interactions of 254 couples to illustrate their use.


[Perceptions and practices related with tuberculosis and treatment compliance in Chiapas, Mexico].
To identify health perceptions and practices and non-adherence to therapy among tuberculosis patients. Qualitative research work consisting of 11 group interviews with 62 tuberculosis patients during 1997-1998 in the Central, Highlands, and Border Regions of Chiapas, Mexico. Perceived causes of tuberculosis included contagion via food utensils, excess work, malnutrition, and cold, as well as other causes unrelated to person-to-person contagion. The resulting incapability to work resulted in an economic crisis for both the patients and their family members. As a result of the social stigma imposed by the disease, patients perceived a negative impact on their personal life, family, work, and community. Lack of knowledge regarding tuberculosis is an important factor in the selection of and adherence to different care alternatives. Inadequate care provided by health services, including an unsatisfactory physician-patient relationship, resulted in diagnostic delay and non-adherence to therapy. Education programs to promote basic knowledge regarding tuberculosis and its treatment are necessary in this region.


[Chromatographic behavior of fat-soluble vitamin in reversed phase liquid chromatography with water-isopropanol mobile phase].
The separation of a mixture fat-soluble vitamin A, D, E by reversed-phase HPLC on elution with an isopropanol-water was studied. A procedure was developed for determining vitamin mixtures and was applied to the analysis of 9 multivitamin tablet. The vitamin was fully separated in 15 min using a short C18 column and UV detection at 280 nm. Different solvent were used for sample extraction. The recoveries were measured, and were higher than 95%. Experimental results proved that the three fat-soluble vitamin A, D, E all can be fully eluted by a solution of isopropanol-water in the ratio of 75%:25%.


The -318 C>G single-nucleotide polymorphism in GNAI2 gene promoter region impairs transcriptional activity through specific binding of Sp1 transcription factor and is associated with high blood pressure in Caucasians from Italy.
Inhibiting Galpha subunit 2 protein, which is encoded by the GNAI2 gene, is suggested to be pathogenic for essential hypertension and/or insulin resistance. The aim of this study was to determine whether GNAI2 variations modulate the risk for these abnormalities. Seven single-nucleotide polymorphisms (SNP) at the GNAI2 locus were identified. Because of either low allelic frequency or unlikely biologic relevance (i.e., synonymous or intronic), six SNP were not studied further. The -318C>G SNP (allelic frequency 6%) in the promoter region was studied for association with adiposity, systolic BP (SBP) and diastolic BP, fasting insulin and glucose, and lipids levels in 655 nondiabetic Caucasians from Italy. As compared with individuals who carry the C/C genotype, G carriers (i.e., individuals who carry either the G/G or the C/G genotype) had higher SBP (117.8 +/- 16 versus 113.6 +/- 12.6 mmHg; P = 0.010) and were at increased risk for hypertension (odds ratio 2.2; 95% confidence interval 1.1 to 4.5). Compared with the C, the G allele had 2.5-fold reduced transcriptional activity in transfected HEK293 cells. As predicted by the TRANSFAC database, competition with YY1 or Sp1 transcription factors specifically reduced the binding of HeLa cell nuclear proteins to -318C or -318G allele, respectively, as indicated by shifted electrophoretic mobility. A "supershift" of the nuclear proteins/-318G allele complex was observed after anti-Sp1 was added but not anti-YY1 antibody. The GNAI2 -318 C>G SNP impairs transcriptional activity through specific binding of Sp1 and is associated with high SBP in Caucasians from Italy.


Ursodeoxycholate and tauroursodeoxycholate inhibit cholangiocyte growth and secretion of BDL rats through activation of PKC alpha.
Accumulating bile acids (BA) trigger cholangiocyte proliferation in chronic cholestasis. The aim of this study was to determine if ursodeoxycholate (UDCA) or tauroursodeoxycholate (TUDCA) chronic feeding prevents the increased cholangiocyte growth and secretion in bile duct-ligated (BDL) rats, if UDCA and TUDCA effects are associated with increased cholangiocyte apoptosis, and to determine if this inhibition is dependent on increased intracellular Ca(2+) ([Ca(2+)](i)) and activation of protein kinase C (PKC) alpha. Immediately after BDL, rats were fed UDCA or TUDCA (both 275 micromol/d) for 1 week. We determined the number of bile ducts in liver sections, cholangiocyte proliferation (by measurement of H(3) histone and proliferating cellular nuclear antigen in isolated cholangiocytes), and ductal secretion. In purified cholangiocytes from 1-week BDL rats, we evaluated if UDCA and TUDCA directly inhibit cholangiocyte proliferation and secretin-stimulated adenosine 3', 5'-monophosphate levels. We determined if UDCA and TUDCA activate PKC, increase [Ca(2+)](i), and alter the apical BA transporter (ABAT) expression in cholangiocytes. UDCA and TUDCA inhibited in vivo the cholangiocyte proliferation, secretion, and ABAT expression. In vitro UDCA and TUDCA inhibition of cholangiocyte growth and secretion required increased [Ca(2+)](i) and PKC alpha. In conclusion, activation of Ca(2+)-dependent PKC alpha is required for UDCA and TUDCA inhibition of cholangiocyte growth and secretion. Reduced cholangiocyte ABAT may decrease endogenous BA stimulation of cholangiocyte growth and secretion.


Pseudocalculus sign. A pitfall of static cholangiography.
The pseudocalculus formation was first noted by Caroli in 1960, and was first called a sign by Beneventano and Schein in 1968. It is a cholangiographic illusion that appears as a filling defect in the distal common bile duct when static or "spot" films are exposed during the contractile phase of choledochal sphincter activity. Although first noted and most frequently seen in T-tube cholangiography, it is seen also during intravenous and intraoperative cholangiography. Because it mimics radiographically an impacted stone in the distal common bile duct, its delineation is critical to avoid unnecessary instrumentation of the common bile duct or even reoperation. In this review the authors discuss briefly the anatomy and physiology of the distal common bile duct and the etiology, differential diagnosis, and recognition of the pseudocalculus sign.


Fibromodulin Interacts with Collagen Cross-linking Sites and Activates Lysyl Oxidase.
The hallmark of fibrotic disorders is a highly cross-linked and dense collagen matrix, a property driven by the oxidative action of lysyl oxidase. Other fibrosis-associated proteins also contribute to the final collagen matrix properties, one of which is fibromodulin. Its interactions with collagen affect collagen cross-linking, packing, and fibril diameter. We investigated the possibility that a specific relationship exists between fibromodulin and lysyl oxidase, potentially imparting a specific collagen matrix phenotype. We mapped the fibromodulin-collagen interaction sites using the collagen II and III Toolkit peptide libraries. Fibromodulin interacted with the peptides containing the known collagen cross-linking sites and the MMP-1 cleavage site in collagens I and II. Interestingly, the interaction sites are closely aligned within the quarter-staggered collagen fibril, suggesting a multivalent interaction between fibromodulin and several collagen helices. Furthermore, we detected an interaction between fibromodulin and lysyl oxidase (a major collagen cross-linking enzyme) and mapped the interaction site to 12 N-terminal amino acids on fibromodulin. This interaction also increases the activity of lysyl oxidase. Together, the data suggest a fibromodulin-modulated collagen cross-linking mechanism where fibromodulin binds to a specific part of the collagen domain and also forms a complex with lysyl oxidase, targeting the enzyme toward specific cross-linking sites.


Loteprednol etabonate (submicron) ophthalmic gel 0.38% dosed three times daily following cataract surgery: integrated analysis of two Phase III clinical studies.
To evaluate the efficacy and safety of a submicron formulation of loteprednol etabonate (LE) gel 0.38% instilled three times daily (TID) compared with vehicle for the treatment of inflammation and pain following cataract surgery with intraocular lens implantation, integrated across two multicenter, double-masked, randomized, parallel-group, Phase III studies. Subjects ≥18 years of age with anterior chamber (AC) cells ≥grade 2 (6-15 cells) on day 1 after cataract surgery were randomized to receive 1 drop of LE gel 0.38% TID, twice daily (not reported/analyzed herein), or vehicle instilled in the study eye for 14 days. Primary endpoints were the proportion of subjects with resolution of AC cells and grade 0 (no) pain at postoperative day 8. Safety outcomes included adverse events (AEs), ocular signs, fundoscopy results, visual acuity, intraocular pressure (IOP), and tolerability (drop comfort and ocular symptoms). The integrated intent-to-treat population included 742 subjects (LE gel 0.38% TID, n=371; vehicle, n=371). Significantly more subjects in the LE gel 0.38% TID group compared with the vehicle group had complete resolution of AC cells (29.6% vs 15.1%) and grade 0 pain (74.4% vs 48.8%) at day 8 (P<0.0001 for both). LE gel 0.38% TID was safe and well tolerated, with only 1 LE-treated subject experiencing an IOP elevation ≥10 mm Hg. Most treatment-related AEs were mild and occurred less frequently with LE gel 0.38% than with vehicle. The majority (>75%) of subjects in each treatment group reported no drop discomfort. There were no reports of blurred vision with LE gel. The results of this integrated analysis indicate that LE (submicron) gel 0.38% administered TID is safe and effective for the treatment of ocular inflammation and pain following cataract surgery, with minimal risk of IOP elevation.


Engineering novel complement activity into a pulmonary surfactant protein.
Complement neutralizes invading pathogens, stimulates inflammatory and adaptive immune responses, and targets non- or altered-self structures for clearance. In the classical and lectin activation pathways, it is initiated when complexes composed of separate recognition and activation subcomponents bind to a pathogen surface. Despite its apparent complexity, recognition-mediated activation has evolved independently in three separate protein families, C1q, mannose-binding lectins (MBLs), and serum ficolins. Although unrelated, all have bouquet-like architectures and associate with complement-specific serine proteases: MBLs and ficolins with MBL-associated serine protease-2 (MASP-2) and C1q with C1r and C1s. To examine the structural requirements for complement activation, we have created a number of novel recombinant rat MBLs in which the position and orientation of the MASP-binding sites have been changed. We have also engineered MASP binding into a pulmonary surfactant protein (SP-A), which has the same domain structure and architecture as MBL but lacks any intrinsic complement activity. The data reveal that complement activity is remarkably tolerant to changes in the size and orientation of the collagenous stalks of MBL, implying considerable rotational and conformational flexibility in unbound MBL. Furthermore, novel complement activity is introduced concurrently with MASP binding in SP-A but is uncontrolled and occurs even in the absence of a carbohydrate target. Thus, the active rather than the zymogen state is default in lectin.MASP complexes and must be inhibited through additional regions in circulating MBLs until triggered by pathogen recognition.


Development of the ASK-20 adherence barrier survey.
Poor medication adherence is widespread among patients with chronic conditions requiring long-term drug therapy. Medication adherence is determined by multiple patient-, context-, and therapy-dependent factors. This paper describes the development and initial validation of the ASK-20 survey, created to identify actionable risk factors for medication nonadherence and to improve communication about adherence. A pool of 30 items was generated through comprehensive literature review. Items were refined and the item pool was expanded through an expert panel review and patient focus groups to yield 47 candidate items, each with five response options ranging from either Strongly Agree to Strongly Disagree or from In the Last Week to Never. The pool of 47 candidate items was administered to a web-based sample of 605 patients taking medications and reporting a diagnosis of asthma, diabetes, or depression for psychometric testing and item reduction. Eleven multi-item factor groupings with two additional unique items were identified on the basis of principal components analysis and interpretability. Twenty (20) items representing ten factor groupings were selected for the final instrument. Each of the final items was dichotomized as positive - indicating a barrier, or negative. Two summary scores - the sum of all positive barriers or Total Barrier Count (TBC) and the sum of raw item scores, the ASK-20 score - were calculated. Concurrent validity of the dichotomously scored individual items, the TBC and ASK-20 scores in relation to self-reported adherence was generally good. Cronbach's alpha coefficient was 0.77 for the TBC and 0.85 for the ASK-20 score. ASK-20 consists of 20 clinically actionable items representing multiple factors that affect medication adherence. The ASK-20 survey demonstrated satisfactory validity and internal consistency and may be used to identify actionable barriers to adherence across a spectrum of chronic diseases. Future research using more objective measures of adherence is warranted to confirm the exploratory validity and reliability of ASK-20 reported in this study.


A multicenter comparison of cognitive-behavioral therapy and interpersonal psychotherapy for bulimia nervosa.
Research suggests that cognitive-behavioral therapy (CBT) is the most effective psychotherapeutic treatment for bulimia nervosa. One exception was a study that suggested that interpersonal psychotherapy (IPT) might be as effective as CBT, although slower to achieve its effects. The present study is designed to repeat this important comparison. Two hundred twenty patients meeting DSM-III-R criteria for bulimia nervosa were allocated at random to 19 sessions of either CBT or IPT conducted over a 20-week period and evaluated for 1 year after treatment in a multisite study. Cognitive-behavioral therapy was significantly superior to IPT at the end of treatment in the percentage of participants recovered (29% [n=32] vs 6% [n=71), the percentage remitted (48% [n=53] vs 28% [n = 31]), and the percentage meeting community norms for eating attitudes and behaviors (41% [n=45] vs 27% [n=30]). For treatment completers, the percentage recovered was 45% (n= 29) for CBT and 8% (n= 5) for IPT. However, at follow-up, there were no significant differences between the 2 treatments: 26 (40%) CBT completers had recovered at follow-up compared with 17 (27%) IPT completers. Cognitive-behavioral therapy was significantly more rapid in engendering improvement in patients with bulimia nervosa than IPT. This suggests that CBT should be considered the preferred psychotherapeutic treatment for bulimia nervosa.


Regulation of caspase-3 and -9 activation in oxidant stress to RTE by forkhead transcription factors, Bcl-2 proteins, and MAP kinases.
Cytotoxicity to renal tubular epithelial cells (RTE) is dependent on the relative response of cell survival and cell death signals triggered by the injury. Forkhead transcription factors, Bcl-2 family member Bad, and mitogen-activated protein kinases are regulated by phosphorylation that plays crucial roles in determining cell fate. We examined the role of phosphorylation of these proteins in regulation of H(2)O(2)-induced caspase activation in RTE. The phosphorylation of FKHR, FKHRL, and Bcl-2 family member Bad was markedly increased in response to oxidant injury, and this increase was associated with elevated levels of basal phosphorylation of Akt/protein kinase B. Phosphoinositol (PI) 3-kinase inhibitors abolished this phosphorylation and also decreased expression of antiapoptotic proteins Bcl-2 and BclxL. Inhibition of phosphorylation of forkhead proteins resulted in a marked increase in the proapoptotic protein Bim. These downstream effects of PI 3-kinase inhibition promoted the oxidant-induced activation of caspase-3 and -9, but not caspase-8 and -1. The impact of enhanced activation of caspases by PI 3-kinase inhibition was reflected on accelerated oxidant-induced cell death. Oxidant stress also induced marked phosphorylation of ERK1/2, P38, and JNK kinases. Inhibition of ERK1/2 phosphorylation but not P38 and JNK kinase increased caspase-3 and -9 activation; however, this activation was far less than induced by inhibition of Akt phosphorylation. Thus the Akt-mediated phosphorylation pathway, ERK signaling, and the antiapoptotic Bcl-2 proteins distinctly regulate caspase activation during oxidant injury to RTE. These studies suggest that enhancing renal-specific survival signals may lead to preservation of renal function during oxidant injury.


Electronic phenomena at complex oxide interfaces: insights from first principles.
Oxide interfaces have attracted considerable attention in recent years due to the emerging novel behavior which does not exist in the corresponding bulk parent compounds. This opens possibilities for future applications in oxide-based electronics and spintronics devices. Among the different materials combinations, heterostructures containing the two simple band insulators LaAlO(3) and SrTiO(3) have advanced to a model system exhibiting unanticipated properties ranging from conductivity, to magnetism, even to superconductivity. Electronic structure calculations have contributed significantly towards understanding these phenomena and we review here the progress achieved in the past few years, also showing some future directions and perspectives. A central issue in understanding the novel behavior in these oxide heterostructures is to discover the way (or ways) that these heterostructures deal with the polar discontinuity at the interface. Despite analogies to polar semiconductor interfaces, transition metal oxides offer much richer possibilities to compensate the valence mismatch, including, for example, an electronic reconstruction. Moreover, electronic correlations can lead to additional complex behavior like charge disproportionation and order, magnetism and orbital order. We discuss in some detail the role of finite size effects in ultrathin polar films on a nonpolar substrate leading to another intriguing feature-the thickness-dependent insulator-to-metal transition in thin LaAlO(3) films on a SrTiO(3)(001) substrate, driven by the impending polar catastrophe. The strong and uniform lattice polarization that emerges as a response to the potential build-up enables the system to remain insulating up to a few layers. However, beyond a critical thickness there is a crossover from an ionic relaxation to an electronic reconstruction. At this point two bands of electron and hole character, separated both in real and in reciprocal space, have been shifted sufficiently by the internal field in LaAlO(3) to impose the closing of the bandgap. We discuss briefly further parameters that allow one to manipulate this behavior, e.g. via vacancies, adsorbates or an oxide capping layer.


Multimodal control of sensors on multiple simulated unmanned vehicles.
The use of multimodal (speech plus manual) control of the sensors on combinations of one, two, three or five simulated unmanned vehicles (UVs) is explored. Novice controllers of simulated UVs complete a series of target checking tasks. Two experiments compare speech and gamepad control for one, two, three or five UVs in a simulated environment. Increasing the number of UVs has an impact on subjective rating of workload (measured by NASA-Task Load Index), particularly when moving from one to three UVs. Objective measures of performance showed that the participants tended to issue fewer commands as the number of vehicles increased (when using the gamepad control), but, while performance with a single UV was superior to that of multiple UVs, there was little difference across two, three or five UVs. Participants with low spatial ability (measured by the Object Perspectives Test) showed an increase in time to respond to warnings when controlling five UVs. Combining speech with gamepad control of sensors on UVs leads to superior performance on a secondary (respond-to-warnings) task (implying a reduction in demand) and use of fewer commands on primary (move-sensors and classify-target) tasks (implying more efficient operation). STATEMENT OF RELEVANCE: Benefits of multimodal control for unmanned vehicles are demonstrated. When controlling sensors on multiple UVs, participants with low spatial orientation scores have problems. It is proposed that the findings of these studies have implications for selection of UV operators and suggests that future UV workstations could benefit from multimodal control.


Perceived ethnicity and the risk of compulsory admission.
Black-Caribbean patients are more often admitted compulsorily to psychiatric wards than patients from other ethnic groups. We tested the hypothesis that perceived ethnicity of a patient had no independent effect on the risk of compulsory admission. For all consecutive admissions over a 6-month period to acute psychiatric wards in Nottingham, medical officers responsible for the decision to admit completed a questionnaire recording clinical details of the patients and reasons for admission. The results showed that 43.2% of Black-Caribbean patients and 18.8% of White patients were admitted compulsorily (unadjusted odds ratio 3.29, 95% CI 1.71-6.33). Perceived ethnicity (Black-Caribbean) was significantly associated with being young, receiving a diagnosis of psychosis, and being perceived to be at a risk of violent acting out. A forced entry logistic regression model was used to adjust for hypothesised confounding variables such as age, sex, diagnosis, risk, socio-economic status and level of social support. A diagnosis of psychosis, risk of committing violence and being Black-Caribbean had independent effects on the risk of being compulsorily detained. The odds ratio for compulsory detention of Black-Caribbean patients was 2.16 (95% CI 1.03-4.52) after adjusting for the hypothesised confounding variables.


Bioactive polymers grafted on silicone to prevent Staphylococcus aureus prosthesis adherence: in vitro and in vivo studies.
As joint prostheses become infected preventive strategies are needed. Silicone prostheses were coated with a COO - and SO3 - bearing bioactive copolymer, Q5, synthesized by radical polymerization and the adherence of Staphylococcus aureus (S. aureus)to them was evaluated in vitro and in vivo. Copolymer Q5 contains tris(trimethylsiloxy) methacryloxy propyl silane favoring the compatibility with the silicone matrix, cinnamoyl ethyl methacrylate allowing a network formation at the surface of the silicone prostheses, two ionic monomers: methacrylic acid and sodium styrene sulfonate. In vitro experiments were conducted on Q5-coated silicone lenses and on Q5-coated silicone prostheses. In both cases, materials were incubated with fi-bronectin (Fn) because of its important role in S. aureus adherence to implant surfaces. The percentage of adhesion inhibition was observed at approximately 40% for the coated materials compared to the untreated silicone. Rabbits underwent double-blind partial knee replacements with Q5-coated or control implants fitted into the intramedullary canal of the tibia, and 10 7 bacteria were injected into the knees. The number of bacteria adherent on the prostheses was determined 24 hr later. Signifi-cantly fewer bacteria adhered to Q5-coated than control prostheses (2.26 +/- 0.76 vs 3.86 +/- 0.54 log10 CFU/ml; p < 0.0035). Bioactive polymer coating could provide a new method of preventing joint-prosthesis infections. (Journal of Applied Biomaterials & Biomechanics 2003; 1: 178-85).


Effect of iodonium salt and chitosan on the physical and antibacterial properties of experimental infiltrants.
Resinous infiltrants are indicated in the treatment of incipient carious lesions, and further development of these materials may contribute to greater control of these lesions. The aim of this study was to analyze the physical and antibacterial properties of experimental infiltrants containing iodonium salt and chitosan. Nine experimental infiltrants were formulated by varying the concentration of the diphenyliodonium salt (DPI) at 0, 0.5 and 1 mol%; and chitosan at 0, 0.12 and 0.25 g%. The infiltrants contained the monomeric base of triethylene glycol dimethacrylate and bisphenol-A dimethacrylate ethoxylate in a 75 and 25% proportion by weight, respectively; 0.5 mol% camphorquinone and 1 mol% ethyl 4-dimethylaminobenzoate. The degree of conversion was evaluated using Fourier transformer infrared spectroscopy, and the flexural strength and elastic modulus using the three-point bending test. Sorption and solubility in water, and antibacterial analysis (minimum inhibitory concentration and minimum bactericidal concentration) were also analyzed. Data was analyzed statistically by two-way ANOVA and Tukey's test (p<0.05), with the exception of the antibacterial test, which was evaluated by visual inspection. In general, the infiltrant group containing 0.5% DPI and 0.12% chitosan showed high values of degree of conversion, higher values of elastic modulus and flexural strength, and lower sorption values in relation to the other groups. Antibacterial activity was observed in all the groups with DPI, regardless of the concentration of chitosan. The addition of DPI and chitosan to experimental infiltrants represents a valid option for producing infiltrants with desirable physical and antibacterial characteristics.


[The prehistory of mathematics and the modern mind: mathematical thought and resourcefulness in the Palaeolithic Franco-Cantabrian region].
In the present article, we begin by reviewing the different types of symbolic records produced by prehistoric groups from the oldest probable origins of the modern human mind. Next, we review some of the most outstanding prehistoric pieces related to counting, enhancing the relevance (both quantitatively and qualitatively) of this type of piece in the Franco-Cantabrian region. These reviews lead us finally to note the tremendous relevance, within this context, of four horse-bone plaques from the Altamira Cave, dated in the Solutrean period (18,500 years). These small plaques, apparently constituting a coherent group of interrelated elements, are proposed here as the representation of a recursive process, recursion being a feature proposed as proper and exclusive of human language.