The effect of venous thrombus location and extent on the development of post-thrombotic signs and symptoms.
This prospective study determined the incidence of signs and symptoms of chronic venous disease and recurrent venous thrombotic events (VTE) in relation to the location and extent of the initial venous thrombus. A first episode of acute deep vein thrombosis (DVT) occurred in 120 lower extremities of 105 patients (59 men; mean age, 54 years [range, 23-82 years]). Patients who presented with pain, swelling, or signs and symptoms of pulmonary embolism of <10 days were included. The DVT was diagnosed with duplex ultrasound (DUS) imaging. Patients were grouped by those having thrombosis in one venous segment (group A) or multiple levels (group B). Patients were treated with heparin and warfarin. Patients with at least 1-year of follow-up with clinical and DUS were included. No difference was found in the duration of signs and symptoms at presentation. The median follow-up was 3.4 years (range, 1.2-7 years). More symptomatic limbs were seen in group B (71 of 79) compared with group A (21 of 41; P < .001). Post-thrombotic syndrome (PTS) was more advanced in group B vs group A, including the prevalence of skin damage and ulceration (61 of 79 vs 26 of 41, P < .001; 29 of 79 vs 6 of 41, P = .019, respectively). Limbs with calf DVT that had focal thrombosis were most often asymptomatic. Calf thrombosis in patients with proximal DVT produced the highest prevalence of PTS. Venous claudication was exclusively found in group B and was present only when iliac veins were involved. Recurrent thrombosis had a trend for a higher prevalence in group B (5 of 41 vs 16 of 79, P = .39). Reflux, obstruction, or a combination of the two were more common in group B (61 of 79) vs group A (15 of 41; P < .0001). Limbs with both reflux and obstruction were more likely to develop skin damage (group A, 5 of 6 vs 1 of 35, P < .0001; group B, 24 of 29 vs 5 of 50, P < .0001). Recurrent thrombosis and skin damage is more likely to develop in patients with multiple sites of thrombosis than in those with thrombosis in a single vein segment. Patients with reflux and obstruction presented more skin damage than those with reflux or obstruction alone. Involvement of the calf veins in the presence of proximal vein thrombosis increased the likelihood for PTS.


[Fusion of field and laboratory studies on the investigation of arsenic].
Arsenic is ubiquitously distributed in nature throughout Earth's crust and thus the major source of exposure to this metalloid for the general population is naturally polluted drinking water from wells. In East Asia, more than 30 million people are chronically exposed to arsenic. Interestingly, the manifestations of vascular diseases caused by prolonged exposure to arsenic are consistent with those induced by impaired production of endothelium-derived nitric oxide (NO). However, no information has been available on the relation between NO synthesis and chronic arsenic poisoning in humans. A cross-sectional study in an endemic area of chronic arsenic poisoning in Inner Mongolia and experimental animal studies indicated that long-term exposure to arsenic by drinking water causes reduction of NO production in endothelial cells. Subsequent examinations with rabbits showed that decreased NO production during arsenic exposure is, at least in part, due to an "uncoupling" of endothelial NO synthase evoked by decreased levels of (6R)-5,6,7,8-tetrahydro-L-biopterin (BH(4)), a cofactor of the enzyme, leading to endothelial dysfunction. Furthermore, an intervention study in the area of chronic arsenic poisoning in Inner Mongolia suggested that decreased NO levels and peripheral vascular disease in arsenosis patients can be reversed by exposure cessation. In our cellular experiments, we found that arsenic exposure causes adaptive responses against oxidative stress and arsenic cytotoxicity through Nrf2 activation. This review summarizes the results of our recent studies on a fusion of field and laboratory studies on the chronic arsenic poisoning and cellular protection against the metalloid.


Paracrine interaction in testicular somatic cells.
Initiation of spermatogenesis is regulated by signals derived from intratubular Sertoli cells as well as extratubular Leydig cells, both being systemic targets of hypophyseal gonadotropins. In addition to Leydig and Sertoli cells, a number of other cell types are present in the testis viz. peritubular cells, macrophages and vascular components. The specific paracrine functions of these cells are only partially understood. The peritubular and Sertoli cells form the structural scaffold of the germinal epithelium and are responsible for intratubular pressure, release and transport of spermatozoa and the formation of the blood-testis barrier. We have performed ex vivo and in vitro studies on the ultrastructure of peritubular and Sertoli cells and the distribution of steroid hormone receptors, cytoskeletal and extracellular matrix proteins using rat testes from different stages of postnatal development. Morphological observations were related to in vitro findings of gene expression on the respective hormones and structural proteins. In the developing rat testis, the peritubular cells showed a strong and consistent expression of fibronectin, entactin, laminin as well as the glucocorticoid, androgen, estrogen and partially also the progesterone receptor, while the Sertoli cells were devoid of glucocorticoid receptor and entactin. The glucocorticoid receptor was present in around 20% of the intratubular germ cells (in the 2nd postnatal week) and in 50% of the peritubular cells. In Leydig cells also, the expression reached its climax in the 3rd weak and declined thereafter. This is perhaps pointing to a differentiation-inhibiting role of glucocorticoids in gonocyte differentiation. In the 3rd developmental week, the androgen receptor was present in about 15% of all gonocytes and later in 50% of peritubular cells and about 40% of interstitial cells. The estrogen receptor was absent in peritubular cells of the adult testis. The progesterone receptor was present in about 30% of the peritubular and 25% of the Leydig cells. Taking into account the significant increase in seminiferous tubules following postnatal developmental day 18, the peritubular cells seem to exert an androgen dependent growth stimulus to the seminiferous cords perhaps via the Sertoli cells. In vitro studies of peritubular and Sertoli cells cultured either alone or in co-culture showed by RT-PCR the expression of the androgen and the glucocorticoid receptors in both cell types, as well as fibronectin. Secretion of fibronectin occurred in a clear-cut time-dependent increase in monocultures of peritubular cells (on day 3 of culture). In co-cultures of Sertoli and peritubular cells, fibronectin bio- synthesis was down-regulated. The paracrine interplay between extracellular matrix and hormonal signals joining peritubular and Sertoli cells is essential in the differentiation of the seminiferous tubules.


[Measurement of intracellular pH in long-chain dicarboxylic acid-producing yeast Candida tropicalis and its growth activity].
Intracellular pH (pHi) has an important influence on the metabolic activity of cells or cellular processes. The intracellular pH (pHi) of long-chain alpha,omega-dicarboxylic acid-producing Candida tropicalis was determined by fluorescence technique using a pH-sensitive fluorescent probe 5(6)-carboxyfluorescein diacetate. Optimal loading conditions of the fluorescent probe into the cells were experimentally determined. Effects of extracellular pH and carbon sources for growth on pHi in the cell grown in a flask were studied; the results indicated that extracellular pH has a slight influence on pHi, whereas carbon sources such as sucrose, glucose, acetic acid, and n-tridecane showed moderate influences. Further work on the relationship between the cell growth activity and pHi was carried out in a 5 L bioreactor. The time course of specific rates of the cell growth, glucose consumption, CO2 production, and pH gradients across cell plasma membrane were plotted, where the cell growth was improved by the higher pHi at 8 - 12 h. The measured pHi values were varied from 5.72 to 6.15 at medium pH 6.0 in which glucose and sodium acetate were used together as carbon source. The investigation of pHi can be helpful for understanding its effects on the kinetics of the metabolic steps involved in the synthesis rate of alpha,omega-dicarboxylic acid and alpha,omega-dicarboxylic acid transport across plasma membranes.


Surgical management of patients receiving haemodialysis for chronic renal failure.
This study was carried out on 22 patients seeking dental extractions of one molar tooth. The first group consisted of 12 patients suffering from chronic renal failure undergoing haemodialysis, while the other group consisted of 10 apparently healthy dental patients acting as a control group. The scope of this work is based on the proper handling and management of chronic renal failure patients receiving haemodialysis and undergoing an oral surgical procedure. Complete blood picture, screening of bleeding and coagulation and postextraction complications were monitored for the two groups.


Antihyperglycemic therapy and cardiovascular outcomes after acute myocardial infarction in elderly patients with diabetes.
Type 2 diabetes mellitus is a clear prognostic marker for increased cardiovascular morbidity and mortality after acute myocardial infarction (AMI). We compared diabetes patients based on therapy used (no pharmacotherapy, those prescribed oral antihyperglycemic agents and those prescribed insulin) on the composite risk of recurrent AMI, congestive heart failure and mortality among elderly patients with AMI. Using administrative data, we identified patients, aged 65 years and older, with an incident AMI hospitalization in British Columbia and the Calgary Health Region between April 1, 1995, and March 31, 2002, for a retrospective cohort study. Cox proportional hazard models were constructed to compare time to reach the composite outcome in the treatment groups. Among 22 499 patients with AMI, 5158 patients had diabetes. Women comprised 43.2% of the diabetes cohort. For the composite outcome, there was a stepwise increase in the occurrence based on medication use: no diabetes (23.55 events per 100 person-years); diabetes but no treatment (31.70 per 100 person-years); oral agents only (36.34 per 100 person-years) and insulin therapy (49.43 per 100 person-years). After adjustment, relative to patients without diabetes, no treatment (hazard ratio 1.37, 95% confidence interval, 1.22 to 1.53), oral agents only (hazard ratio 1.43, 95% confidence interval, 1.31 to 1.56) and insulin therapy (hazard ratio 1.65, 95% confidence interval, 1.48 to 1.84) were all associated with an increased risk of the outcome developing. Diabetes conferred a significant risk increase in a combination of cardiovascular events after AMI. The risk existed even for diabetes patients not prescribed therapy and showed a progressive trend as the intensity of treatment advanced toward insulin.


Reservoir computing and extreme learning machines for non-linear time-series data analysis.
Random projection architectures such as Echo state networks (ESNs) and Extreme Learning Machines (ELMs) use a network containing a randomly connected hidden layer and train only the output weights, overcoming the problems associated with the complex and computationally demanding training algorithms traditionally used to train neural networks, particularly recurrent neural networks. In this study an ESN is shown to contain an antagonistic trade-off between the amount of non-linear mapping and short-term memory it can exhibit when applied to time-series data which are highly non-linear. To overcome this trade-off a new architecture, Reservoir with Random Static Projections (R(2)SP) is investigated, that is shown to offer a significant improvement in performance. A similar approach using an ELM whose input is presented through a time delay (TD-ELM) is shown to further enhance performance where it significantly outperformed the ESN and R(2)SP as well other architectures when applied to a novel task which allows the short-term memory and non-linearity to be varied. The hard-limiting memory of the TD-ELM appears to be best suited for the data investigated in this study, although ESN-based approaches may offer improved performance when processing data which require a longer fading memory.


Dietary lysine and carnitine: relation to growth and fatty livers in rats.
Male weanling rats were fed a 72% rice diet containing no detectable carnitine and limiting in threonine and lysine. Such dietary conditions may simulate protein malnutrition in man. Under these conditions growth impairment, anemia, hypoproteinemia, and fatty liver developed. The study focused principally on the fatty liver syndrome which was corrected to varying extents depending on degrees of supplementation with carnitine, lysine, threonine, and appropriate combinations of these nutrients. Such reduction in fatty liver accumulation was accounted for principally by the lowering of triglycerides, but also in part of total cholesterol levels. All the data, which also included monitoring carnitine uptake by the tissues and measurement of plasma triglycerides, were consistent with the view that fatty liver accumulation occurs in amino acid deficient diets because (a) of an impairment in the synthesis of the lipoprotein complex mandatory for triglyceride secretion from the liver and (b) from a deficiency of carnitine needed for the intramitochondrial transport of fatty acids prerequisite for their oxidation.


Conduction blockade in myelinated fibers by gaseous and volatile substances.
The minimum ambient partial pressure required to reversibly disrupt conducted responses in myelinated nerve fibers (Pblock) was determined for 11 gases and chloroform. For all but one substance, Pblock was inversely proportional to their nonaqueous solubility; large-diameter fibers were less vulnerable than fibers of small diameter. No "anesthetic" effect was displayed by SF6. At the Pblock for three of the agents, the time for completion of their anesthetic action (tb) was proportional to their lipid-to-aqueous solubility ratio. When the ratio was large, tb was longer than when the ratio was small; blockade became complete after the partial pressure of the agent in the lipid or nonaqueous phase of the axon membrane became equal to Pblock. The access of these substances to an nonaqueous site was neither pH nor frequency dependent, but in the case of SF6 access did appear to be limited by its molal volume.


Adhesion between neutrophils and platelets: a modulator of thrombotic and inflammatory events?
Recent studies have demonstrated that neutrophilic granulocytes and platelets have the capability to interact with each other. Either type of cell may release soluble factors, which either activate the other or increase its response to separate stimulating agents. Direct contact between the two types of cell generally increases the response, and it may be predicted that neutrophil-platelet adhesion will augment the potential for biochemical interaction in vivo. Adhesion may also promote immobilisation of neutrophils or platelets in thrombotic or inflamed tissue, while circulation aggregates could cause vascular blockage. Adhesion between neutrophils and platelets is dependent on P-selectin on activated platelets and sialyated carbohydrate moieties on the neutrophil, although other molecular mechanisms could stabilise the interaction. The adhesive interaction is strong enough to allow flowing neutrophils to adhere to immobilised platelets, and induce formation of aggregates in vivo. Thus, inhibition of neutrophil-platelet adhesion and modulation of their biochemical interactions could be a novel approach to treatment of thrombotic, ischaemic or inflammatory disorders.


Hyperuricemia, gout and the metabolic syndrome.
The metabolic syndrome is defined by the clustering of a number of cardiovascular risk factors and entails an increased risk for cardiovascular disease and mortality from both cardiovascular disease and all causes. In the present paper, we review the most recent evidence on the association between hyperuricemia, metabolic syndrome, and cardiovascular disease. Serum urate is frequently elevated in patients with the metabolic syndrome and increases with the number of components of this condition. Hyperuricemia has been related to decreased renal uric acid excretion, which may be mediated by enhanced proximal tubular sodium reabsorption and hyperinsulinemia. Recent epidemiologic studies have shed some light on the prognosis of hyperuricemia. While hyperuricemia appears to show a benign significance in low cardiovascular risk individuals, it clearly increases cardiovascular mortality in patients at high cardiovascular disease risk. Clinicians should be aware of the presence of metabolic syndrome in patients with hyperuricemia or gout in order to control its components (high blood pressure, obesity, etc.) and hence reduce the risk for cardiovascular disease. Long-term, randomized interventional clinical trials are needed to test the hypothesis that urate-lowering therapy can reduce cardiovascular risk in these patients.


Tolerability of ziprasidone: an expanding perspective.
Although atypical antipsychotic agents have improved the management of patients with schizophrenia, their utility has been hindered by some limitations, including significant weight gain, glucose metabolism disturbances, and increases in total and low-density lipoprotein cholesterol and triglyceride levels. In addition to its low liability for movement disorders and its favorable tolerability record in short- and long-term clinical trials, ziprasidone is associated with a favorable metabolic safety profile (in terms of its effect on plasma lipid and glucose levels) and a negligible effect on weight. The limited effect of ziprasidone on the corrected QT interval (QTc) has also been well characterized, and experience to date has not demonstrated any increased risk of clinical events attributable to QTc prolongation. This review of pharmacokinetic and clinical trials of ziprasidone versus placebo and active comparators focuses on the safety and tolerability of both the intramuscular and oral formulations.


Peripheral blood stem cell (PBSC) collection in extremely low-weight infants.
While PBSC collection has become a safe procedure for adults, only a few reports exist about its efficacy, safety and feasibility in paediatric patients, especially extremely low-weight infants. We describe successful PBSC collection in three infants of less than 10 kg body weight (BW; range: 6.92-9.4 kg) suffering from stage IV neuroblastoma. Harvest of PBSC started after mobilisation with high-dose chemotherapy and G-CSF, as soon as 1.0% CD34+ cells were detected. Collections were performed using a Baxter CS-3000 Plus separator primed with a mixture of irradiated, white cell-depleted and CMV-negative packed red cells resuspended in 5% human albumin and diluted with saline to match the patient's haematocrit. Performing a median of four, (4-7, median, range) procedures we collected at least 4 x 10(8)/kg BW nucleated cells (NC) from all three patients. The infants were not sedated and showed no serious side-effects. All three children were successfully transplanted with myeloid engraftment in 8 (7-9) days, independence from red cell support was achieved in 15 (10-20) days and from platelet transfusions in 25 (14-29) days after PBSC infusion. We conclude that PBSC harvesting using continuous flow cell separators is safe, even in low-weight infants of less than 7 kg BW.


Diagnosis and localisation of insulinoma: the value of modern magnetic resonance imaging in conjunction with calcium stimulation catheterisation.
Preoperative localisation of insulinoma improves cure rate and reduces complications, but may be challenging. To review diagnostic features and localisation accuracy for insulinomas. Cross-sectional, retrospective analysis. A single tertiary referral centre. Patients with insulinoma in the years 1990-2009, including sporadic tumours and those in patients with multiple endocrine neoplasia syndromes. Patients were identified from a database, and case notes and investigation results were reviewed. Tumour localisation by computed tomography (CT), magnetic resonance imaging (MRI), octreotide scanning, endoscopic ultrasound (EUS) and calcium stimulation was evaluated. Insulinoma localisation was compared to histologically confirmed location following surgical excision. Thirty-seven instances of biochemically and/or histologically proven insulinoma were identified in 36 patients, of which seven were managed medically. Of the 30 treated surgically, 25 had CT (83.3%) and 28 had MRI (90.3%), with successful localisation in 16 (64%) by CT and 21 (75%) by MRI respectively. Considered together, such imaging correctly localised 80% of lesions. Radiolabelled octreotide scanning was positive in 10 out of 20 cases (50%); EUS correctly identified 17 lesions in 26 patients (65.4%). Twenty-seven patients had calcium stimulation testing, of which 6 (22%) did not localise, 17 (63%) were correctly localised, and 4 (15%) gave discordant or confusing results. Preoperative localisation of insulinomas remains challenging. A pragmatic combination of CT and especially MRI predicts tumour localisation with high accuracy. Radionuclide imaging and EUS were less helpful but may be valuable in selected cases. Calcium stimulation currently remains useful in providing an additional functional perspective.


Predictive markers for hepatitis C antibody ELISA specificity in Australian blood donors.
The hepatitis C antibody reactivity rate in 91,748 blood donors tested using the ORTHO HCV C-100 ELISA system was 0.51%. Specificity of ELISA positive reactions was measured using a recombinant immunoblot assay (RIBA). The aim of this study was to identify markers in ELISA positive donors which were predictive of a RIBA positive result. Samples from 430 ELISA positive donors were tested by the first generation RIBA, RIBA-1, which incorporates two HCV peptides C-100 and 5-1-1. Fifty-five per cent (236) were positive and 19% (83) indeterminate. Multivariate analysis of gender, age, HCV ELISA OD ratio, alanine aminotransferase (ALT) status and hepatitis B core antibody (anti-HBc) status identified age, magnitude of HCV ELISA OD ratio and anti-HBc status as the only independent predictors of a positive RIBA-1 result. The relative odds of being RIBA-1 positive were 4.6-fold (95% CI 1.3-16.4) higher among donors aged 25-34 years compared with donors less than 25 or greater than 44; 6.1-fold (2.1-17.9) higher if the donor was anti-HBc positive and 273.4-fold (30.9-2417) higher if the HCV ELISA OD ratio was greater than 5.98 compared to those with a ratio less than 1.77. Seventy-eight of the 83 RIBA-1 indeterminates were tested on the second generation RIBA, RIBA-2, which includes two additional HCV peptide, C22 and C33c. Thirty-one per cent (24) were positive and 41% (32) were negative.(ABSTRACT TRUNCATED AT 250 WORDS)


The young person's guide to biomedical informatics.
In a retrospective review, a parallel is drawn between the challenges by which a research department in biomedical informatics is confronted and those of a symphony orchestra. In both areas, different disciplines and different groups of instruments can be discerned. The importance of mastering one's instrument and the harmony between the team members is stressed. The conductor has to stimulate the individual players so that they can all have a successful career. Competition between orchestras and performance assessments determine survival and success. A record of refereed publications is crucial for continued existence. Conclusions are that biomedical informatics is typically multidisciplinary, that hypotheses underlying research should be carefully formulated, that the time from research to application may easily take 20 years or more, that mutual trust and knowing each other's competences is essential for success, that a good leader gives enough room to all team members to develop their careers, and that the outcomes of assessment studies are related to the quality of publications.


A regional audit of perinatal and infant autopsies in Northern Ireland.
To investigate the rate and quality of perinatal/infant autopsies and their contribution to the final diagnosis. The anonymised reports of autopsies performed on 174 of the 367 cases reported to the Northern Ireland Regional Confidential Enquiry into Stillbirths and Deaths in Infancy (CESDI) coordinator in 1993 were reviewed. They were scored using a modification of the CESDI Pathology Audit Form 93 and, based on the score obtained, ascrined to one of three groups: good, adequate or inadequate. Based on the information obtained, they were also assessed as providing diagnostic, confirmatory, additional or no diagnostic data. The pre-autopsy clinical extended Wigglesworth classification was compared with that based on autopsy findings. The autopsy rate was 47.4% and included 18 late fetal losses, 70 stillbirths, 57 neonatal deaths and 29 post neonatal deaths. The Regional Paediatric Pathology Centre performed 34.5% of the autopsies. Of the total number of autopsies, 46.6% failed to reach an adequate standard. Only 4.9% of the inadequate autopsies were performed in the Regional Centre. The Wigglesworth classification was altered in 20.7% of cases following autopsy. The autopsy findings of 49 cases were diagnostic, 75 confirmatory, 23 yielded additional information and 27 were useful in only a negative sense. The autopsy rate for this region is well below the recommended level of 75%. With the exception of the Regional Centre, the quality of the perinatal/infant autopsy did not reach the standard suggested in the CESDI Pathology Audit form 93. Despite this the autopsy yielded valuable diagnostic, confirmatory or additional findings in 84.5% and resulted in alteration to the pre-autopsy Wigglesworth classification in 20.7%.


Synergism between collagen-adenosine diphosphate and collagen-epinephrine in platelets' aggregation: different dose response relationships.
To evaluate the possible synergistic interaction of collagen-adenosine diphosphate and collagen-epinephrine in aggregation of human platelets. An experimental study was carried out at Armed Forces Instiute of Pathology, Rawalpindi, Pakistan, from June 2001 to December 2002. The platelet aggregation was determined by means of turbidometric method, which measures changes in optical density of platelet suspension. After determining the sub-threshold values of each agonist with the help of dose-response curve, these agonists were added in pairs to determine the synergism between them. The differences between means of threshold and sub-threshold concentrations of agonists were significant (Collagen: P<0.001, ADP: P<0.001, Epinephrine: P<0.002). The responses of Collagen and Epinephrine in sub-threshold concentrations were synergistic in causing platelet aggregation, whereas there were no potentiating effects in response to that of Collagen and Adenosine diphosphate. The study reveals the synergistic potentiation of some of the agonists in circulation that might be responsible for the activated state of platelets and associated atherosclerotic complications.


Inhaled medicinal cannabis and the immunocompromised patient.
Medicinal cannabis is an invaluable adjunct therapy for pain relief, nausea, anorexia, and mood modification in cancer patients and is available as cookies or cakes, as sublingual drops, as a vaporized mist, or for smoking. However, as with every herb, various microorganisms are carried on its leaves and flowers which when inhaled could expose the user, in particular immunocompromised patients, to the risk of opportunistic lung infections, primarily from inhaled molds. The objective of this study was to identify the safest way of using medicinal cannabis in immunosuppressed patients by finding the optimal method of sterilization with minimal loss of activity of cannabis. We describe the results of culturing the cannabis herb, three methods of sterilization, and the measured loss of a main cannabinoid compound activity. Systematic sterilization of medicinal cannabis can eliminate the risk of fatal opportunistic infections associated with cannabis among patients at risk.


Urethral obstruction due to the passage of a retained projectile into the genitounrinary system.
Urethral foreign bodies are relatively rare. When seen, they are usually the result of entry via the urethral meatus. Several reports in the literature have documented the passage of retained bullets into the genitourinary system. The vast majority of these were ultimately expelled spontaneously via the urethra. Very few cases of urethral obstruction and accompanying urinary retention due to bullet migration have been described. The presented case details distal urethral obstruction due to the migration of a retained firearm projectile presenting 1 month after initial gunshot wound. No such case exists in the emergency medicine literature.


Spatial memory in aged rats: population heterogeneity and effect of levocarnitine acetyl.
The existence in a population of aging rats of classes that display a different performance in the Morris water-maze test was investigated by cluster analysis procedure. These classes identified at 18 months of age showed a different response to levocarnitine acetyl and had a different behavioral profile when tested at 25 months of age. These findings demonstrate the need for an alternative interpretation of variability in animal populations as measured by the standard statistical analyses. The data analysis strategy we propose here will allow for the use of variability as a useful source of information.


Accurate in vitro transcriptional initiation of the chick alpha 2 (Type I) collagen gene.
Chick genomic DNA containing the extreme 5' end of the alpha 2 (type I) collagen gene has been used as template in an in vitro HeLa cell transcription system. RNA polymerase II-dependent transcription initiates from a specific site on this DNA. The precise location of this site was determined by three types of experiments: sizing of in vitro-synthesized RNA runoff transcripts, comparing the sequence of the in vitro-made RNA transcripts with the structure of the DNA template, and identifying the first and second nucleotides of the in vitro-synthesized transcripts. Transcription was found to initiate 33 base pairs downstream from a canonical Goldberg-Hogness sequence (TATAAATA). This in vitro start site is the same as the initiation site of in vivo-synthesized collagen RNA.


Mortality in patients with systemic lupus erythematosus in Colombia: a case series.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with high mortality rates. This study aimed to describe the main causes of death in a case series of SLE patients attended in a single center in Colombia. We conducted a retrospective review and analysis of records of SLE patients who died between January 2011 and June 2017. We extracted the main causes of death and described variables associated with this outcome as well as variables associated with the disease and its treatment. From a total of 1776 patients with SLE, we identified 49 fatal cases (89.8% women, n = 44). The average age at death was 40.6 years (SD 17.4), and patients had a median of 4.5 years (IQR 2-8) of disease duration. The main findings included lymphopenia in 44 patients (89.9%), biopsy-confirmed lupus nephritis (LN)-types IV and VI-in 38 (77.6%), catastrophic antiphospholipid syndrome (CAPS) in 8 (16.3%), and persistent hypocomplementemia (C3 and C4) in 8 (16.3%). The median SLE disease activity index (SLEDAI-2K) score at the time of death was 19 (IQR 11-39). The main cause of death was SLE activity and lupus-induced damage in 22 (44.9%) patients. The main causes of death included SLE activity refractory to immunosuppressive treatment, and nosocomial bacterial infections. The patients who died had persistently high SLEDAI scores, types IV and VI LN, associated antiphospholipid syndrome, and persistent hypocomplementemia, requiring severe immunosuppression and prolonged hospitalization.


Risk-adjusted procedure tailoring leads to uniformly low complication rates in ventral and incisional hernia repair: a propensity score analysis and internal validation of classification criteria.
The usual approach in hernia surgery is to select the ideal repair method independent of the patient's characteristics. In the present study, we change the approach to ask which technique is best for the individual patient`s risk profile. For this, two criteria are important: does the patient need reconstruction of the abdominal wall? or does he or she need treatment of symptoms without being exposed to unnecessarily high perioperative risks? In a heuristic selection procedure, 486 consecutive patients were classified according to their characteristics as low-risk or high-risk for postoperative complications. Low-risk patients preferentially underwent open abdominal wall reconstruction with mesh (MFR + mesh), high-risk patients mainly a bridging-mesh procedure, either by laparoscopic (Lap.-IPOM) or open approach (Open-IPOM). Primary outcome was the incidence of postoperative complications. Secondary outcome was the recurrence-free interval. The propensity score was used for covariate adjustment analyzing recurrence rate as well as postoperative complications using Cox regression and logistic regression, respectively. Comparison of all surgical procedures showed risk factors had no independent influence on occurrence of complications (p = 0.110). Hernial gap width was an independent factor for occurrence of complications (p = 0.002). Propensity score adjustment revealed Lap.-IPOM to have a significantly higher recurrence rate than MFR + mesh (HR 2.367, 95% CI 1.123-4.957, p = 0.024). Three or more risk factors were protective against recurrence (HR 0.454, 95% CI 0.221-0.924, p = 0.030). In the univariate Cox regression analysis for recurrence, age >50 years was a protective prognostic factor (HR 0.412, 95% CI 0.245-0.702, p = 0.002). The classification criteria applied were internally validated. The heuristic algorithm ensured that patients at high-risk of complications did not have a higher perioperative complication rate than patients at low-risk.


Carcinogenic effects of intracolonic benzo[a]pyrene in beta-naphthoflavone-induced mice.
Benzo[a]pyrene (BP) was administered intracolonically to ICR/Ha and C57Bl/6 female mice, 1 mg/mouse, once weekly for 14 weeks. Half of the mice received beta-naphthoflavone (beta-NF, a mixed-function oxygenase inducer) i.p. 24 h prior to the BP. No colonic neoplasms were found in any of the mice after 18 months. However, the BP treatment did cause a significant increase in numbers of primary lung tumors, forestomach papillomas, mammary carcinomas, and sarcomas in one or both strains, relative to controls, and the incidence of all of these except for the sarcomas was significantly reduced by treatment with beta-NF prior to BP. Overall, the beta-NF pretreatment reduced total incidence of neoplasms by about 30% in the ICR/Ha mice and by about 60% in the C57Bl/6 mice, and did not potentiate the action of the carcinogen in any organ.


Ca(2+)-mobilizing hormones potentiate hypotonicity-induced activation of ionic conductances in Intestine 407 cells.
Human Intestine 407 cells respond to hyposmotic stimulation by activating the conductive efflux of both Cl- and K+ (regulatory volume decrease) through pathways involving protein tyrosine phosphorylation (Tilly, B. C., N. van den Berghe, L. G. J. Tertoolen, M. J. Edixhoven, and H. R. de Jonge. J. Biol. Chem. 268: 19919-19922, 1993). Stimulation of the cells with hormones linked to the phospholipase C signaling cascade (e.g., bradykinin, histamine, or thrombin) or with the phosphotyrosine phosphatase inhibitor vanadate, potentiated the osmosensitive anion efflux by two- to threefold but did not affect anion efflux under isotonic conditions. No substantial increase in intracellular Ca2+ concentration ([Ca2+]i) was observed on mild hypotonicity-induced cell swelling. In addition, loading the cells with the intracellular Ca2+ chelator 1,2-bis(2-amino-phenoxy)ethane- N,N,N',N',-tetraacetic acid acetoxymethyl ester (BAPTA-AM) caused a partial reduction of the osmoshock-induced 125I- efflux but did not affect its potentiation by vanadate. In contrast, bradykinin transiently elevated [Ca2+]i, and its potentiation of the osmosensitive anion efflux was completely inhibited after BAPTA-AM loading. Both the Ca(2+)-mobilizing hormones as well as osmotic cell swelling rapidly triggered the phosphorylation of several proteins on tyrosine residues. However, the effects of the hormones, but not the effect of hypotonicity, on protein tyrosine phosphorylation was largely abolished in BAPTA-loaded cells. Taken together the results indicate a novel role for Ca(2+)-mobilizing hormones, although elevation of [Ca2+]i, in potentiating volume-sensitive ionic efflux even in cell types lacking the expression of Ca(2+)-activated Cl- channels in their plasma membrane.


Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome.
Cushing's syndrome (CS) is associated with central adiposity, insulin resistance and impaired glucose homeostasis. Adipose tissue is thought to regulates glucose homeostasis via circulating adipokines, such as resistin, leptin and adiponectin, although their role in the insulin resistance associated with CS has not been established. We examined the relationship between insulin resistance and adipokine levels in CS patients. We compared plasma levels of resistin, leptin and adiponectin in 10 women and four men patients with CS, with 14 health subjects matched for age, gender and body mass index. A subgroup of three women and four men with pituitary-dependent CS were re-examined at least 9 months after curative surgery. CS patients had significantly more truncal fat and less lean body mass as assessed by DEXA compared to control subjects. Total cholesterol, triglycerides and insulin resistance, as calculated using the homeostasis model assessment of insulin resistance (HOMA-R), was significantly increased in CS patients. Of the adipokines measured, only resistin was significantly different between female CS patients and female control subjects (5.05 +/- 0.56 vs. 2.91 +/- 0.39 micro g/l, P = 0.015). Curative surgery significantly reduced total body fat and truncal fat, leptin, total and low-density lipoprotein (LDL) cholesterol, glucose and HOMA-R. A reduction in both resistin and adiponectin was also observed but the differences between pre- and post-treatment levels did not achieve statistical significance. Here we report for the first time that resistin levels are significantly elevated in CS patients and may be important in the insulin resistance associated with glucocorticoid excess.


Modelling the mitigation speeds of 137Cs, 90Sr and 131I in the topsoils and assessment of the radiological hazards.
Fate modelling of artificial radionuclides (ARs) in top soils are necessary to assess the radiological effects to population. Among ARs, 137Cs, 90Sr and 131I are very important since the large abundances in the environment. In this study, the fates of 137Cs, 90Sr and 131I in the surface soil layers were simulated by the soil model which was developed by the Canadian Centre for Environmental Modelling and Chemistry (CEMC). The scenario that 137Cs, 90Sr and 131I contaminated in topsoil in the exclusion of Fukushima Daiichi nuclear power plant (NPP) accident was evaluated. The results show the expected time for the minimum hazardous level of exposure. It is 115.5 days after the exposure, when the total effective dose is 1 mSv y-1 in which 0.46 mSv y-1 from ingestion and 0.54 mSv y-1 from gamma exposure. Hazard levels due to exposure progresses are varied in order gamma exposure (82.14%) > ingestion (17.47%) > inhalation (0.39%). The hazard levels from radionuclides are varied in order 137Cs (63.34%) > 131I (33.48%) > 90Sr (3.18%).


High-temperature gating of solid-state nanopores with thermo-responsive macromolecular nanoactuators in ionic liquids.
Stimuli-responsive nanofluidic systems in room temperature ionic liquids (RTILs). The nanofluidic device can withstand high temperatures up to 200 °C, in which conventional water-based smart materials and nanodevices are invalid. The smart nanopores can be "irreversibly" turned off above the transition temperature of ca. 120-150 °C, actuated by the conformational change of the chemically-modified polymer brushes.


Template-selective stimulation of diverse DNA polymerases by the murine DNA-binding protein factor D.
Factor D, a template-selective DNA polymerase-alpha stimulatory protein from mouse liver (Fry, M., Lapidot, J., and Weisman-Shomer, P. (1985) Biochemistry 24, 7549-7556) is shown here to enhance the activities of diverse DNA polymerases with a cognate template specificity. DNA synthesis catalyzed by Escherichia coli DNA polymerase I, avian myeloblastosis virus polymerase, and some mammalian alpha- and gamma-polymerases was increased by factor D. With every enhanced polymerase, factor D increased the rate of copying of only poly(dT) among various tested synthetic poly-deoxynucleotides. Of the natural DNA templates examined, rates of copying of sparsely primed denatured DNA and of singly primed circular phi X174 or M13 bacteriophage DNA, but not of activated DNA, were enhanced. Michaelis constants (Km) of affected templates with responsive polymerases were decreased by factor D, without alteration in maximum velocity (Vmax). By contrast, factor D increased Vmax of deoxyribonucleoside 5'-monophosphate incorporation without changing Km of deoxyribonucleoside 5'-triphosphate substrates. Binding of factor D to poly(dT), poly(dA).poly(dT), and DNA, but less to poly(dA), was indicated by specific retention of their complexes on a DEAE-cellulose column. That factor D does not bind to DNA polymerase-alpha or to its complex with the DNA template was demonstrated by the failure of the factor to be coprecipitated with alpha-polymerase by anti-polymerase-alpha monoclonal antibodies in either the absence or presence of various templates. Lack of binding of factor D to the polymerase molecule was also indicated by simultaneous maximum stimulation of two competing polymerases by a limiting amount of factor. These combined results suggest that the enhancement of DNA synthesis is exerted through interaction of factor D with the template. It is proposed that this association leads to a tighter binding of the polymerase to the template and facilitates DNA synthesis.


Review of measures of neuropathic pain.
Eight measures of neuropathic pain exist that have been designed to discriminate neuropathic from non-neuropathic pain and detect treatment effects. The current paper describes these measures and summarizes the evidence supporting their validity. Based on the available evidence, the Leeds Assessment of Neuropathic Signs and Symptoms appears to have the most empirical support as a measure that distinguishes patients with and without neuropathic pain in patient samples presenting with mixed chronic pain problems. However, given the lack of overlap in measures designed for this purpose, it is likely that the validity of any one measure could be improved by incorporating items from the others. The Neuropathic Pain Scale (NPS) has the most empirical support as a measure of treatment outcome, although a new measure that includes the NPS items (the Pain Quality Assessment Scale) will likely prove to be even more useful, because it includes pain descriptors common to people with neuropathic and other chronic pain conditions not included on the NPS.


Taperosis: Does head length affect fretting and corrosion in total hip arthroplasty?
Tribocorrosion at the head-neck taper interface - so-called 'taperosis' - may be a source of metal ions and particulate debris in metal-on-polyethylene total hip arthroplasty (THA). We examined the effect of femoral head length on fretting and corrosion in retrieved head-neck tapers in vivo for a minimum of two years (mean 8.7 years; 2.6 to 15.9). A total of 56 femoral heads ranging from 28 mm to 3 mm to 28 mm + 8 mm, and 17 femoral stems featuring a single taper design were included in the study. Fretting and corrosion were scored in three horizontally oriented concentric zones of each taper by stereomicroscopy. Head length was observed to affect fretting (p = 0.03), with 28 mm + 8 mm femoral heads showing greater total fretting scores than all other head lengths. The central zone of the femoral head bore taper was subject to increased fretting damage (p = 0.01), regardless of head length or stem offset. High-offset femoral stems were associated with greater total fretting of the bore taper (p = 0.04). Increased fretting damage is seen with longer head lengths and high-offset femoral stems, and occurs within a central concentric zone of the femoral head bore taper. Further investigation is required to determine the effect of increased head size, and variations in head-neck taper design.


The effect and mode of action of zinc pyrithione on cell growth. I. In vitro studies.
The effects of zinc pyrithione (ZnPTO) were studied in a series of in vitro tests to determine whether its mode of action is primarily cytostatic or cytotoxic. Sodium pyrithione (NaPTO) was also studied, to check that pyrithione was the active moiety, and the known cytostatic chemical hydroxyurea was included for comparison. ZnPTO had a reversible inhibitory effect on the growth of BHK 21 cells at 0.1 microgram/ml, but had a rapid, irreversible inhibitory effect at 1 microgram/ml associated with cell rounding and detachment. NaPTO produced a similar effect but hydroxyurea produced an essentially reversible inhibition even at a dose well above that producing complete inhibition. ZnPTO and NaPTO both caused contraction, rounding and blebbing of BHK 21 cells in perfusion-chamber tests, at higher levels (1 and 10 micrograms/ml) than required for growth inhibition, but only 10 micrograms ZnPTO/ml caused lactate dehydrogenase (LDH) release. Hydroxyurea had no effects in these tests. ZnPTO and NaPTO also reduced the survival of Chinese hamster V79 cells sharply over a narrow dose range (0.01-0.03 microgram/ml), but the effect of hydroxyurea was not as sharp and occurred at much higher doses. All three showed elements of cytostasis and cytotoxicity as demonstrated by analysis of the relationship between survival and colony area. Of the three, only ZnPTO (at greater than or equal to 5 micrograms/ml) caused significant LDH release from the cells, though both ZnPTO and NaPTO (at 0.1-1 microgram/ml) inhibited cell growth as indicated by total LDH values. In studies with rat peritoneal mast cells, ZnPTO and NaPTO (at 10 ng/ml) both suppressed histamine release induced by 48/80 or Ca ionophore A23187, though neither caused histamine release directly. The combined results of these tests show that ZnPTO is primarily cytotoxic, rather than cytostatic.


A conceptual framework for the impact of obesity on risk of cesarean delivery.
Cesarean deliveries accounted for 32.2% of nearly 4 million births in the United States in 2014. Obesity affects a third of reproductive-age women and is associated with worse cesarean delivery outcomes. Studies have shown that increasing maternal body mass index correlates linearly with cesarean delivery rates, but little is known about the potential mediating and moderating mechanisms. Thus, a conceptual framework for understanding how obesity correlates with risk of cesarean delivery is crucial to determining safe ways to reduce the cesarean delivery rate among obese gravidas. Based on an extensive review and synthesis of the literature, we present a conceptual framework that posits how obesity may operate through several pathways to lead to a cesarean delivery. Our framework explores the complexity of obesity as an exposure that operates through potential mediating pathways, a moderator of cesarean delivery risk, and a covariate with other cesarean delivery risk factors. Among nulliparas, obesity appears to operate through 3 main proximal mediating mechanisms to increase risk of cesarean delivery including: (1) preexisting comorbidities and obstetric complications; (2) a slower progression of first-stage labor, potentially increasing the risk of cesarean delivery secondary to failure to progress; and (3) a prolongation of pregnancy, which is associated with risk of maternal postdates. For multiparas, a fourth proximal mediator of prior uterine scar may also increase cesarean delivery risk. Distal mediating mechanisms, which operate through one of the proximal mechanisms, may include an induction of labor or planned prelabor cesarean delivery. Obesity may also moderate the likelihood of cesarean delivery by interacting with clinician-level or hospital-level factors. Future research should assess the validity of this framework and seek to understand the relative contributions of each potential pathway between obesity and cesarean delivery. This will allow for evidence-based recommendations to reduce preventable cesareans among obese women by targeting modifiable mediators and moderators of the relationship between obesity and increased risk of cesarean delivery.


Detection of circulating tumor necrosis factor after endotoxin administration.
Cytokines, products of stimulated macrophages, are thought to mediate many host responses to bacterial infection, but increased circulating cytokine concentrations have not been detected consistently in infected patients. We measured plasma concentrations of circulating tumor necrosis factor alpha (cachectin), interleukin-1 beta, and gamma interferon, together with physiologic and hormonal responses, in 13 healthy men after intravenous administration of Escherichia coli endotoxin (4 ng per kilogram of body weight) and during a control period of saline administration. Eight additional subjects received ibuprofen before receiving endotoxin or saline. Plasma levels of tumor necrosis factor were generally less than 35 pg per milliliter throughout the control period, but increased 90 to 180 minutes after endotoxin administration to mean peak concentrations of 240 +/- 70 pg per milliliter, as compared with 35 +/- 5 pg per milliliter after saline administration. Host responses were temporally associated with the increase in circulating tumor necrosis factor at 90 minutes, and the extent of symptoms, changes in white-cell count, and production of ACTH were temporally related to the peak concentration of tumor necrosis factor. Ibuprofen pretreatment did not prevent the rise in circulating tumor necrosis factor (mean peak plasma level, 170 +/- 70 pg per milliliter) but greatly attenuated the symptoms and other responses after endotoxin administration. Concentrations of circulating interleukin-1 beta and gamma interferon did not change after endotoxin administration. We conclude that the response to endotoxin is associated with a brief pulse of circulating tumor necrosis factor and that the resultant responses are effected through the cyclooxygenase pathway.


Low frequency of PAX8-PPARγ rearrangement in follicular thyroid carcinomas in Japanese patients.
Paired-box gene 8 (PAX8)-peroxisome proliferator-activated receptor-γ (PPARγ) gene fusion has been identified at significant frequency in follicular thyroid carcinomas (FTCs) with cytogenetically detectable translocation t(2;3)(q13;p25). This represents a possible specific molecular marker for follicular carcinoma. In this study, we examined PAX8-PPARγ rearrangement in 24 FTC samples from Japanese patients by reverse transcribed-polymerase chain reaction (RT-PCR) using two upstream PAX8 primers located in exons 7 and 8 and a downstream primer in exon 1 of PPARγ. The fusion gene was detected in only one of 24 FTCs (4%). The FTC with PAX8-PPARγ rearrangement from a 56-year-old man showed a product consistent with fusion between exon 8 of PAX8 and exon 1 of PPARγ. It was confirmed by direct sequencing. This FTC was histologically encapsulated, composed of trabeculae and small follicles and had complete penetration of the capsule by tumor tissues (minimally invasive type). The frequency of the fusion gene in this study was much lower than the 29-63% noted in reports from other countries suggesting that FTCs in Japanese patients may have a special genetic background, and that the high iodine intake from a typical Japanese diet might influence the frequency of the fusion gene in FTCs.


Management of refractory congestive heart failure.
Despite recent advances in the treatment of congestive heart failure (CHF), many patients continue to present with symptoms refractory to digoxin, diuretic, and vasodilatory therapy. Since it is unlikely that this population will decrease in the near future, practical approaches to management of refractory CHF are reviewed. Refractory CHF here is defined as New York Heart Association (NYHA) functional class III-IV heart failure, despite maximal drug therapy. Before such a diagnosis is made, the patient should be treated with digoxin, diuretics, and a vasodilator. Approach to therapy requires assessment of changing clinical status and pathophysiology, optimizing oral drug treatment, and providing temporary parenteral support when indicated. Specific attention should be given to factors that influence the optimal response to each of these 3 treatment classes. A theoretical, but unproven, concept suggests that combined vasodilatory therapy may be appropriate as long as excessive hypotension is avoided. In the course of management, a decision is required as to whether further optimization of therapy can be achieved on an outpatient basis. Hospital-based intravenous inotropic support given for 2-4 days will often provide the opportunity to restructure patient therapy.


Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database.
In the recent past, concerns have raised regarding the potential risk of acute pancreatitis among type 2 diabetic patients using incretin-based drugs such as glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP-4) inhibitors. The aim of this study is to investigate the association between exposure to incretin-based drugs and the occurrence of pancreatitis reported in the French Pharmacovigilance Database. The case/non-case method was performed from serious adverse drug reactions (ADRs) involving antihyperglycemic agents (except insulin alone) reported to the French pharmacovigilance system between March 2008 (first marketing of an incretin-based drug in France) and March 2013. Cases were defined as reports of pancreatitis, and all other serious ADRs were considered non-cases. Disproportionality was assessed by calculating reporting odds ratios (ROR) adjusted for age, gender, history of pancreatitis, other antihyperglycemic drugs and other drugs associated with a higher risk of pancreatitis. Among 3,109 serious ADRs, 147 (4.7 %) reports of pancreatitis were identified as cases and 2,962 reports (95.3 %) of other ADRs as non-cases. Among the cases, 122 (83.0 %) involved incretin-based drugs. Disproportionality was found for all incretin-based drugs (adjusted ROR: 15.7 [95 % CI 9.8-24.9]), all GLP-1 analogs (29.4 [16.0-53.8]), exenatide (28.3 [12.8-62.3]), liraglutide (30.4 [15.4-60.0]), all DPP-4 inhibitors (12.1 [7.3-20.0]), sitagliptin (12.4 [7.3-21.0]), saxagliptin (15.1 [4.3-52.7]), and vildagliptin (7.4 [3.1-17.6]). Temporal analysis found disproportionality for incretin-based drugs since their first year of marketing in France. Compared with other antihyperglycemic agents, use of incretin-based drugs is associated with an increased risk of reported pancreatitis in France.


Clomipramine and obsessive-compulsive disorder.
Clomipramine is a tricyclic antidepressant that was the first effective agent in the treatment of OCD. Its capacity to block serotonin reuptake appears to be essential to reducing the primary symptoms of OCD. Like other tricyclic agents, CMI has an array of possible side effects including gastrointestinal, autonomic, hepatic, and cardiac problems that need to be considered in the clinical management of children and adolescents treated with CMI. Evaluation of clinical response begins with the identification of target symptoms and monitoring the change in these target symptoms over time. This effort can be aided by the use of clinical rating instruments such as the Children's Yale-Brown Obsessive Compulsive Scales and, to a limited degree, drug plasma levels. Although many OCD patients manifest a positive response to CMI, some patients do not. This variation suggests that other neurochemical systems may be implicated in OCD.


Feeding time and body temperature interactions in broiler breeders.
Four groups of 70-wk-old broiler breeder females were fed once daily at 0600, 1000, 1400, and 1800 h to determine the effect of feeding time and eating on body temperature. The photoperiod was from 0430 to 1930 h. Four floor pens of 30 hens each were assigned per feeding time. Following a 9-day adjustment period, body temperature was determined, in series, by rectal probe of 5 birds/pen at 7 and 3 h prefeeding and 1, 5, 9, and 13 h postfeeding. Body temperature was increased .5 C at 1 h postfeeding in all groups and at 5 h postfeeding in the 0600-h fed group. The rate of feed consumption was fastest with afternoon feeding. Four 1-yr-old broiler breeder males were implanted with an FM radio transmitter for monitoring body temperature and housed in an environmental control chamber. Body temperature was monitored when the birds were fed at 0600, 1000, 1400, and 1800 h. The chamber temperature cycled from 22.2 to 33.3 C (22.2 C: 2200 to 0800 h; 33.3 C: 1200 to 1600 h; 27.8 C: 0800 to 1200 h and 1600 to 2200 h). Lights were on from 0430 to 1930 h. Body temperature changes were also monitored under constant temperature (27.8 C) and light for birds fed ad libitum or at 1000 h. Body temperature increased as much as 1.5 C following feeding and reached a maximum at 5, 4, 3, and 2 h postfeeding at feeding times of 0600, 1000, 1400, and 1800 h, respectively. Males unable to feed displayed a significantly increased body temperature when they observed other birds eating. A specific body temperature response to feeding activity was observed only when males were fed once daily under constant environment.


Mediating the contradiction of d33 and TC in potassium-sodium niobate lead-free piezoceramics.
For potassium-sodium niobate, the piezoelectric constant (d33) was usually improved by sacrificing the Curie temperature (TC). In this work, a material system of 0.992(K0.46Na0.54)0.965Li0.035Nb(1-x)Sb(x)O3-0.008BiScO3 has been designed and prepared with the aim of achieving both a large d33 and a high TC at the same time. The chemical compositions are found to be homogeneously distributed in the ceramics. The introduction of Sc is found to be responsible for different grain sizes. The rhombohedral-tetragonal phase coexistence zone lies in the composition range of 0.02<x ≤ 0.06. The ceramic is thermally stable in terms of ferroelectric properties. The change in the domain-wall activities induced by the configuration variation of defect dipoles upon annealing is believed to be responsible for the variation in the d33 at different temperatures. The ceramic with x = 0.025 shows a good comprehensive performance of d33 ≈ 325 pC/N and k(p) ≈ 48%, together with a high T(C) of ~358 °C, demonstrating that this material system is a promising candidate for high-temperature piezoelectric applications.


Usefulness of serum concentration measurement for acute pentobarbital intoxication in patients.
Toxicokinetic parameters were analyzed in 25 patients who were acutely intoxicated with pentobarbital. The serum pentobarbital concentrations were at hypnotic / therapeutic levels (1- 10 microg/mL) in 11 patients, at toxic levels (10-24 microg/mL) in 10 patients, and at lethal levels (>24 microg/mL) in 4 patients. One fatal case was encountered with a serum pentobarbital concentration of 37.27 microg/ mL. The relationships between serum pentobarbital concentrations and the drug, the induced toxic symptoms, such as respiratory / cardiac depression and hypotension, were in good correlation. The therapy of direct hemoperfusion carried out for many pentobarbital-intoxicated patients was highly effective.


Effects of surface nano-topography on human osteoblast filopodia.
Anchorage-dependent cells growing over a substratum require stable adhesion areas on the surface for the next cellular activities. The adhesion is achieved by some contact points called focal adhesions. Because focal adhesions were distributed randomly, a trial to control the positions of focal adhesion with a specific order may cause interesting effects like as cytoskeleton rearrangement, which may induce and transfer new signals to the nucleus. Here, we cultured human osteoblasts over two sorts of nanopatterned surfaces with different pattern densities fabricated by using laser interference lithography and the nanoimprinting technique. Of the two nanopatterns, cells over the nanopattern with low pattern density showed relatively higher adaptation to the topography with guided filopodia protrusion. However, cells over the dense nanopattern showed difficulty in finding suitable paths for migration, as judged from the activities of filopodium formation and the presence of a shovel-like feature at the tip of each filopodium.


Brain injury and neurologic sequelae: a cohort study of dementia, parkinsonism, and amyotrophic lateral sclerosis.
We reviewed the medical records of 821 Olmsted County residents who had suffered head trauma with presumed brain injury between 1935 and 1974 and were more than 40 years old at the time of their last medical assessment. These patients were followed over 15,000 person-years for dementia and other degenerative neurologic diseases. The standardized morbidity ratio (SMR) for dementia was 1.06, and the SMR for dementia of the Alzheimer type was 1.00. These values are not significantly elevated and are inconsistent with studies that suggest that head trauma is a risk factor for Alzheimer's disease. In addition, the SMRs for parkinsonism (1.04), Parkinson's disease (0.94), and amyotrophic lateral sclerosis (1.05) were not significantly elevated, providing no evidence that head trauma is a risk factor for these disorders. However, these latter results are based on smaller total case numbers.


Toxic and mutagenic influences on spermatogenesis.
Cells at various stages of spermatogenesis show remarkable differences in their sensitivities to toxic and mutagenic agents. For accurate analyses of toxicity and mutagenicity, the most sensitive cell types should be obtained for studies soon after treatment before development of disturbing secondary alterations. The transillumination phase contrast microscopic technique has proved to be useful for this purpose. It allows recognition of rat and mouse seminiferous tubules in living unstained conditions for accurate selection of the desired stages of the cycle of the seminiferous epithelium for morphological and biochemical studies. Specific cell damage can be frequently recognized by transillumination only, whereas in most cases phase contrast microscopy is useful in screening the early stage-specific toxic alterations. A summary is presented of the results obtained by treatment with heat and with anticancer drugs. A meiotic micronucleus method has been developed for direct estimation of the severity of mutagenic insult on rat spermatogenesis. The segment that contains the second meiotic division and the early postmeiotic cells (stages XIV and I) is selected for study. Chromosome damage induced by mutagens may result in the formation of acentric fragments that after meiotic divisions are seen in early spermatids as separate micronuclei. They can be quantitated in squash preparations; the sensitivity of this method is comparable with that of the meiotic metaphase scoring. Recently, an in vitro technique has been developed for stage and cell specific measurements of replicative and repair syntheses of DNA during rat spermatogenesis after mutagen treatments.


Regulation of lac operon expression in mixed sugar chemostat cultures.
Expression of the lactose (lac) operon in the Escherichia coli chromosome has been studied in mixed-sugar chemostat cultures under steady-state and transient conditions. A unified model has been formulated which involves regulation of active inducer (lactose) transport, promoter-operator regulated expression of the lac operon, glucose-mediated inducer exclusion, and catabolite repression. The model of the lac operon control system focuses on the molecular interactions among the regulatory species and the genetic control elements for the initiation of transcription. The role of catabolite modulator factor (CMF) in the regulation of transcription is described. The modeling of glucose-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP) and inducer exclusion is based on the recently elucidated mechanisms of the involvement of the PTS (phosphoen-olpyruvate dependent sugar transport system) enzymes, in the presence of glucose, in regulation of adenylate cyclase and non-PTS sugar transport proteins (i.e. per-meases). The adequacy of the unified model was verified with experimental data.


Pi-conjugation in donor-substituted cyanoethynylethenes: an EDA study.
Pi-conjugation in several donor-substituted cyanoethynylethenes was estimated using energy decomposition analysis (EDA); very good linear correlations between the DeltaE(pi) values and experimental data are found.


Effects of sign characteristics and training methods on safety sign training effectiveness.
This study investigated whether or not training methods affected the effectiveness of symbol training and if there were any relationships between sign symbol characteristics and training effectiveness. Altogether, 26 Mainland China industrial safety signs were used and 60 participants were randomly assigned into four equal-sized groups of control, paired-associate learning, recall training and recognition training. The result was that participants from all the training groups showed significantly greater improvement in comprehension performance than those in the control group, indicating that the training methods improved comprehension of the meaning of safety signs. Participants from the recall training group performed better in the post-training test than those from other training groups. It seems that the recall task elicited a deeper level of learning than the recognition task and that questioning and feedback had a positive effect on training effectiveness. The results also showed that sign characteristics had no significant influence on training effectiveness. It was concluded that recall training is more effective in enhancing comprehension of industrial safety signs than paired-associate learning or recognition training. The findings of this study provide a basis for useful guidelines for designing symbol-training programmes and for designing more user-friendly safety signs. STATEMENT OF RELEVANCE: The present study shows that recall training was more effective in improving comprehension of industrial safety signs than paired-associate learning or recognition training and cognitive sign features did not influence training effectiveness. They provide a basis for useful guidelines for designing symbol-training programmes and for designing more user-friendly safety signs.


Glucose-dependent insulinotropic polypeptide and its role in obesity.
As we strive to improve our understanding of the factors that contribute to the pathogenesis of obesity, it is certainly logical to speculate that a nutrition-dependent component emanating from the gastrointestinal tract, which has the capacity to regulate insulin expression, could represent an etiologic factor in this serious health issue. One such regulatory peptide that possesses these properties is glucose-dependent insulinotropic polypeptide. Release of this peptide is stimulated by the ingestion of glucose and fat from the upper portion of the small intestine, which in turn enhances the release of insulin from the pancreas. In addition to its indirect effects in inducing obesity through the stimulation of insulin, a potent efficiency hormone, glucose-dependent insulinotropic polypeptide, like insulin, also directly modulates a variety of factors that are important in adipocyte homeostasis. Such factors include lipoprotein lipase, Akt, and GLUT-4, all of which promote the storage of fat. In this review, various mechanisms by which glucose-dependent insulinotropic polypeptide may serve as a link that indirectly and directly contributes to the development of obesity will be discussed. Understanding the peptide's role will potentially help provide novel ways to prevent and treat obesity.


[DNA synthesis and content in the macrophage nuclei of normal mice, during carcinogenesis and during the administration of retinoids to the animals].
It has been found that nearly 50% of the lymph node and spleen macrophages (MP) of the CBA line mice contain DNA at levels superior to the diploid value (H2c--H4c in mononuclear MP, and up to H16c among polynuclear ones, the latter comprising 2.5-9.0% of the whole MP population). No DNA synthesis and mitosis were detected by autoradiography, cytophotometry, and cytomorphological analysis. During carcinogenesis the proportion of MP with elevated DNA amounts ("activated MPs") decreases due to their migration to tumours. Also immature MPs (1.6%) appear in the population, which synthesize DNA, but do not divide. Injection of retinoids restores the percentage of MPs with elevated DNA amounts to the levels characteristic of the intact animals, the fraction of DNA-synthetizing cells increasing up to 2.8%. It is proposed that retinoids may accelerate the processes of MP maturation, activation and renewing. A mechanism of cooperative action of MPs and retinoids is discussed in addition to the role of DNA hyper-replication.


Pharmacokinetics of pyrrole-imidazole polyamides after intravenous administration in rat.
The pharmacokinetics of pyrrole (Py)-imidazole (Im) polyamides was studied in rats after the intravenous administration of these compounds. Py-Im polyamide (A) was composed of Ac-ImPyPy-ImPyPy-beta-Dp (beta: beta-alanine, Dp: N,N-dimethylaminopropylamide). Py-Im polyamide (B) was composed of Ac-PyIm-beta-ImIm-PyPy-beta-PyPy-beta-Dp. Py-Im polyamide (C) was composed of Ac-PyPy-beta-PyImPy-PyPyPy-beta-ImPy-beta-Dp. The molecular weight of Py-Im polyamide (A) was 1035.12, that of Py-Im polyamide (B) was 1422.51 and that of Py-Im polyamide (C) was 1665.78. After the intravenous injection of Py-Im polyamide (A) at 1.3, 2.0, 7.5 and 15.0 mg/kg, Py-Im polyamides (B) and (C) at 1.0, 2.0, 3.0 and 5.0 mg/kg, the average systemic clearance and the volume of distribution at the steady state obtained by a non-compartmental method were in the ranges of 4.6-6.4 ml/min/kg and 244-412 ml/kg, 8.9-10.3 ml/min/kg and 1990-4567 ml/kg, and 7.3-11.9 ml/min/kg and 407-667 ml/kg, respectively. Dose linearity of Py-Im polyamides was observed. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamides (A) and (B) were fitted well by a two-compartment model. Py-Im polyamide (C) was observed at high concentrations in the lungs. The plasma concentration-time profiles after the intravenous administration of Py-Im polyamide (C) were described using a catenary two-compartment model. This model is useful for describing the time course after the administration of high-molecular-weight Py-Im polyamides.


Origin and compensation of imaging artefacts in localization-based super-resolution microscopy.
Interpretation of high resolution images provided by localization-based microscopy techniques is a challenge due to imaging artefacts that can be categorized by their origin. They can be introduced by the optical system, by the studied sample or by the applied algorithms. Some artefacts can be eliminated via precise calibration procedures, others can be reduced only below a certain value. Images studied both theoretically and experimentally are qualified either by pattern specific metrics or by a more general metric based on fluorescence correlation spectroscopy.


Extremely low birth weight infants with patent ductus arteriosus: searching for the least invasiveness.
Patent ductus arteriosus (PDA) is an important problem in premature infants. Extremely low birth weight infants (ELBWI) are so fragile with respect to surgical stress that minimally invasive procedures are required. We report 26 ELBWI cases with PDA who underwent surgical closure. All had failed indomethacin treatment, or it had been contraindicated. The mean gestational age at birth was 27 weeks (range, 24-38 weeks), and the mean birth weight was 960.96 g (range, 710-1440 g). The mean age at operation was 18.06 days (range, 7-34 days), and the mean body weight at operation was 989.42 g (range, 680-1460 g). There was no surgery-related mortality or morbidity. Our surgical procedures consisted of posterior muscle-sparing thoracotomy, clipping the PDA and no ligation, and closing the thorax without a tube thoracostomy. Muscle-sparing thoracotomy reduces the likelihood of long-term physical impairment and deformity, the clipping technique minimizes the dissection of surrounding PDA tissue, and the thorax is closed without a tube. Nursing care is simplified, costs are reduced, and the number of chest x-rays needed postoperatively is reduced. We believe that surgical closure of PDA without chest tube drainage can be accomplished safely in premature infants.


Impact of insulin pump therapy on long-term glycemic control in a pediatric Spanish cohort.
To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. Retrospective longitudinal study including ninety patients [10.5 (6.5-13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 ± 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 ± 1.8 at one year of CSII to 6.7 ± 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort.


Relationships between changes in plasma lipid transfer proteins and apolipoprotein B-100 kinetics during fenofibrate treatment in the metabolic syndrome.
The aim of the present study was to investigate the association between changes in apoB (apolipoprotein B-100) kinetics and plasma PLTP (phospholipid transfer protein) and CETP (cholesteryl ester transfer protein) activities in men with MetS (the metabolic syndrome) treated with fenofibrate. Eleven men with MetS underwent a double-blind cross-over treatment with fenofibrate (200 mg/day) or placebo for 5 weeks. Compared with placebo, fenofibrate significantly increased the FCRs (fractional catabolic rates) of apoB in VLDL (very-low-density lipoprotein), IDL (intermediate-density lipoprotein) and LDL (low-density lipoprotein) (all P<0.01), with no significant reduction (-8%; P=0.131) in VLDL-apoB PR (production rate), but an almost significant increase (+15%, P=0.061) in LDL-apoB PR. Fenofibrate significantly lowered plasma TG [triacylglycerol (triglyceride); P<0.001], the VLDL-TG/apoB ratio (P=0.003) and CETP activity (P=0.004), but increased plasma HDL (high-density lipoprotein)-cholesterol concentration (P<0.001) and PLTP activity (P=0.03). The increase in PLTP activity was positively associated with the increase in both LDL-apoB FCR (r=0.641, P=0.034) and PR (r=0.625, P=0.040), and this was independent of the fall in plasma CETP activity and lathosterol level. The decrease in CETP activity was positively associated with the decrease in VLDL-apoB PR (r=0.615, P=0.044), but this association was not robust and not independent of changes in PLTP activity and lathosterol levels. Hence, in MetS, the effects of fenofibrate on plasma lipid transfer protein activities, especially PLTP activity, may partially explain the associated changes in apoB kinetics.


A clustering of prostatic cancer in an area with many manganese mines.
In the process of our mass screening trials for prostatic diseases, a significant clustering of prostatic cancer in a town in the suburbs of Kyoto was detected. Upon survey a possible association was found between the locations where the patients lived and the manganese ore deposits distributed in the town.


Immunohistochemical localization of tissue inhibitor of metalloproteinases-2 (TIMP-2) in first trimester human placental decidua.
Matrix metalloproteinases have been shown to play an important role both in the invasive growth of malignant tumors and in human placentation. However, unlike tumor cell invasion, cytotrophoblast invasion is strictly controlled in its extent. Tissue inhibitors of metalloproteinases (TIMP) may play an important role in the modulation of cytotrophoblast growth into maternal tissue. We have undertaken an immunohistochemical study of the distribution of TIMP-2 in the decidua of first trimester human pregnancy. Moderate to strong staining for TIMP-2 was found in decidual stromal cells and the walls of blood vessels in all cases. No unequivocal staining of decidual leukocytes was seen. These findings suggest that TIMP-2 secretion in first trimester human decidua is confined to certain cell populations. Decidual stromal cells are probably an important source of TIMP and may contribute to the regulation of human cytotrophoblast invasion in vivo.


Alteration of gastric ulcerogenic and healing responses in rats with adjuvant-induced arthritis.
Gastroenteropathy is the most common among patients who use non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of inflammatory disorders. It is known that rheumatoid arthritic patients are more susceptible to NSAID-induced gastropathy than other NSAID users. This article reviewed our recent studies concerning the influence of arthritic conditions on gastric ulcerogenic response to NSAID and healing response of chronic gastric ulcers in rats. Gastric lesions induced by indomethacin, one of the conventional NSAIDs, were markedly aggravated in arthritic rats. This increased ulcerogenic response in arthritic rats was attributable to nitric oxide production due to up-regulation of inducible nitric oxide synthase. In arthritic rat stomachs, cyclooxygenase (COX)-2 was also up-regulated, where COX-2 selective inhibitors such as rofecoxib or celecoxib provoked gross lesions, although they caused no damage in normal rats. In addition, the healing of chronic gastric ulcers was also delayed in arthritic rats because of less expression of various growth factors such as basic fibroblast growth factors or insulin-like growth factors. Based on these findings, it is concluded that arthritic conditions alter the mucosal ulcerogenic and healing responses in the stomach. Especially, caution should be paid on the use of COX-2 selective inhibitors in rheumatoid arthritic patients.


Morphologic and functional abnormalities in patients with Ebstein's anomaly with cardiac magnetic resonance imaging: Correlation with tricuspid regurgitation.
The aim of this study was to assess the correlations of functional and dimensional parameters with the severity of tricuspid regurgitation in patients with Ebstein's anomaly (EA) by using cardiac magnetic resonance (CMR) imaging. Thirty-three patients with EA without previous cardiac surgery and 25 normal individuals were recruited and underwent both cardiac MR imaging and preoperative transthoracic echocardiography. The left ventricular (LV) functional parameters and dimensions of the right ventricle (RV) and LV were measured using 3.0-T cardiac MR imaging. Tricuspid regurgitation severity grading was estimated by echocardiography. The functional and dimensional parameters were compared between EA patients and controls using independent sample t-tests. Spearman's rank correlation was used to determine the correlations between the functional and dimensional parameters and tricuspid regurgitation. Receiver operating characteristic (ROC) analysis was used to predict tricuspid regurgitation severity using individual functional and dimensional parameters. Statistical analysis revealed significant differences in the functional and dimensional parameters between EA patients and controls. Within the EA group, tricuspid valve regurgitation negatively correlated well with the left ventricular ejection fraction (LVEF) (r=-0.558, p=0.001). The ratio of the right ventricular (functional right ventricle) end-diastolic dimension to the left ventricle end-diastolic dimension (RVEDD/LVEDD) in EA patients also correlated well with the severity of tricuspid valve regurgitation (r=0.492, p=0.004). Moreover, ROC analysis revealed that high sensitivity and specificity were obtained for predicting the severity of tricuspid valve regurgitation with LVEF (78.3%, 90.0%) and RVEDD/LVEDD (78.3%, 94.3%). In EA patients, the left and right ventricular functional and dimensional parameters from MRI correlated well with tricuspid regurgitation, which helped predict the severity of EA.


Optically trapping confocal Raman microscopy of individual lipid vesicles: kinetics of phospholipase A(2)-catalyzed hydrolysis of phospholipids in the membrane bilayer.
Phospholipase A2 (PLA2)-catalyzed hydrolysis at the sn-2 position of 1,2-dimyristoyl-sn-glycero-3-phosphocholine in optically trapped liposomes is monitored in situ using confocal Raman microscopy. Individual optically trapped liposomes (0.6 microm in diameter) are exposed to PLA2 isolated from cobra (Naja naja naja) venom at varying enzyme concentrations. The relative Raman scattering intensities of C-C stretching vibrations from the trans and gauche conformers of the acyl chains are correlated directly with the extent of hydrolysis, allowing the progress of the reaction to be monitored in situ on a single vesicle. In dilute vesicle dispersions, the technique allows the much higher local concentration of lipid molecules in a single vesicle to be detected free of interferences from the surrounding solution. Observing the local composition of an optically trapped vesicle also allows one to determine whether the products of enzyme-catalyzed hydrolysis remain associated with the vesicle or dissolve into solution. The observed reaction kinetics exhibited a time lag prior to the rapid hydrolysis. The lag time varied inversely with the enzyme concentration, which is consistent with the products of enzyme-catalyzed lipid hydrolysis reaching a critical concentration that allows the enzyme to react at a much faster rate. The turnover rate of membrane-bound enzyme determined by Raman microscopy during the rapid, burst-phase kinetics was 1200 s(-1). Based on previous measurements of the equilibrium for PLA2 binding to lipid membranes, the average number of enzyme molecules responsible for catalyzing the hydrolysis of lipid on a single optically trapped vesicle is quite small, only two PLA2 molecules at the lowest enzyme concentration studied.


High levels of medical utilization by ambulatory patients with vocal cord dysfunction as compared to age- and gender-matched asthmatics.
To evaluate medical utilization by ambulatory patients with vocal cord dysfunction (VCD). Retrospective, case-control study. Pulmonary disease clinic at an army tertiary-care center. Twenty-five ambulatory patients with VCD (mean age, 41 years; range, 27 to 69 years) who were age- (+/- 3 years) and gender-matched to 25 control patients with moderate persistent asthma. Medical utilization for the year preceding the diagnosis of VCD or asthma was obtained from a computerized medical record. End points included total outpatient visits, evaluations by subspecialty physicians, presentations for urgent care, hospitalizations, and number of prescriptions. Total physician visits (477 visits vs 267 visits, respectively; p < 0.004) and subspecialty care visits (277 visits vs 118 visits; p < 0.007) were significantly greater among the VCD cohort as compared with the asthmatic cohort. The groups were also found to have comparable utilization of prescriptions (448 prescriptions vs 394 prescriptions, respectively; p < 0.63), frequency of hospitalizations (seven hospitalizations vs five hospitalizations; p < 0.59), and urgent care visits (45 visits vs 20 visits; p < 0.14). Ambulatory VCD patients use significantly more medical provider resources and similar pharmaceutical assets as compared to patients with moderate persistent asthma.


[Balloon dilatation of aortic coarctation].
Endovascular balloon dilatation of coarctation of the aorta is a manipulation for radical correction of the anomaly with an evident hemodynamic effect in patients with the isolated form, in combination of coarctation of the aorta with aortic stenosis, and in atypical forms of the anomaly. Up to 90% of good immediate results were produced among these patients. Balloon dilatation may also be conducted in recoarctation after the traditional surgical management. Being devoid of some of the negative factors of the accepted methods of treatment, endovascular angioplasty is a sparing and a relatively safe method. Paradoxical hypertension does not develop as a rule. Rare complications in the zone of the approach were encountered. Balloon dilatation may be combined with endovascular correction of other anomalies, and may be repeated many times. In recoarctation and atypical forms of the anomaly balloon dilatation helps in avoiding complex and dangerous operations using the traditional methods. Coarctation in the form of a diaphragm is the most "favourable" type of the anomaly for balloon dilatation. The operation is also indicated in coarctation in patients with hypoplasia of the arch and isthmus, despite its palliative character.


Working with Oligonucleotide Arrays.
Preprocessing microarray data consists of a number of statistical procedures that convert the observed intensities into quantities that represent biological events of interest, like gene expression and allele-specific abundances. Here, we present a summary of the theory behind microarray data preprocessing for expression, whole transcriptome and SNP designs and focus on the computational protocol used to obtain processed data that will be used on downstream analyses. We describe the main features of the oligo Bioconductor package, an application designed to support oligonucleotide microarrays using the R statistical environment and the infrastructure provided by Bioconductor, allowing the researcher to handle probe-level data and interface with advanced statistical tools under a simplified framework. We demonstrate the use of the package by preprocessing data originated from three different designs.


Development of coated tubes RIA for serum T3 (tri-iodothyronine) for production scale.
A coating procedure that could provide immobilization of antibodies, with increased binding capacity, that is cost effective, simple, robust, and appropriate for production scale application, is described. This coating approach of T3 antibodies to the polystyrene tubes has been systematically investigated to determine its utility for the development of coated tube Radioimmunoassay (RIA) for T3 in human serum. Further, the results obtained by the developed coating procedure are found to be comparable with those obtained by the "gold standard," the liquid phase RIA for T3. The coating procedure is completed in three major steps, each step involving an overnight incubation. The normal rabbit gamma-globulins are physically adsorbed onto the polystyrene tubes and incubated. After washing, a second antibody (goat anti-rabbit antiserum) is added and incubated. To this antigen specific antibody is added (T3 antibody produced in rabbit) and further incubated. Finally, the non-specific sites on the tubes are saturated by the blocking solution. The concentration of normal rabbit globulin, titers of second antibody and T3 antibody, and time required for coating are optimized to arrive at a suitable coating protocol. The coated tubes were evaluated for precision, reproducibility, and stability. Various parameters such as total reaction volume, incubation time and temperature, total number and volume of washings, concentration of 8-anilino-1-naphthalene sulfonic acid (ANS), and quantity of tracer per tube are optimized to arrive at a suitable standard curve. The optimized assay is validated for the quality control parameters such as intra- and inter-assay variations, recovery, and parallelism. The developed coated tubes assay had an assay range of 0.3-4.8 ng/mL with a sensitivity of 0.3 ng/mL at 90% B/B0. Batch to batch variation in coating was < 10%. The coated tubes were stable up to 1 year, which is adequate for production scale.


[Atipical form of Mayer-Rokitansky-Kuster-Hauser syndrome with renal malformation and skeletal abnormalities (MURCS association)].
The atypical and more severe form of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) or MRKH type II is also known as MURCS association, an acronym meaning aplasia/hypoplasia of Müllerian ducts (MU), congenital renal dysplasia (R) and cervico-thoracic dysplasia (CS). It affects female patients with normal karyotype and ovarian function, evolving to primary amenorrhea. It has an incidence of 1:50,000, but it is underestimated due to late diagnosis and undefined etiology. We describe the cases of a child and an adolescent in order to predict the diagnosis even in childhood, before the onset of amenorrhea. Patients had in common renal malformation, agenesis or hypoplasia of Müllerian derivatives and vertebral anomalies, establishing the diagnosis of MURCS. The relevance of this paper is to show the importance of further investigation when some of pathologic signs are present, researching correlated abnormalities in order to establish an early diagnosis and consequently to provide guidance to the patients and their families about the best way to conduct the case, including genetic counseling.


Anterior lumbar inter-body fusion with instrumentation compared with posterolateral fusion for low grade isthmic-spondylolisthesis.
Spondylolisthesis presenting as low back pain is not an uncommon condition. Many of such patients are treated conservatively. For those that require surgical management, various treatment options are in vogue e.g. Postero-lateral fusion (PLF) with decompression or posterior fusion with instrumentation and anterior lumbar inter-body fusion (ALIF). Each technique has produced satisfactory outcome with benefits and disadvantages. To compare the outcome of surgical management of low grade spondylolisthesis with two treatments modalities--Postero-lateral fusion (PLF) and Anterior lumbar inter-body fusion (ALIF) with posterior instrumentation in similar patient profile. Prospective study to compare the results of two surgical treatment modalities. The selected group of patients for surgery based on definite criteria was operated by the same surgeon by two modalities: Postero-lateral fusion with decompression and Anterior Lumbar Inter-body fusion with posterior instrumentation. The outcomes were compared. Analysis of variance (ANOVA) test. Follow up was done at twelve weekly intervals up to 2 years. Both groups showed good recovery in pain as seen in Visual analogue scale (VAS) and Oswestry low back pain scoring. Intra-operative bleeding was observed to be higher in Postero-lateral fusion group. Average length of hospital stay for the patients of PLF group was 6.6 days (Range: 4-7 days) as compared to 12.5 days (Range: 10-16 days) in case of ALIF group. Treatment cost was found to be higher in patients who undergone ALIF with instrumentation. ALIF with posterior instrumentation in low grade isthmic spondylolisthesis provides satisfactory outcome in patients requiring surgical treatment. The results of pain relief and disability index are comparable to time tested posterolateral fusion. ALIF shows a tendency to faster pain relief and return to activity with less intraoperative blood requirement in low grade isthmic spondylolisthesis.


The structural basis for induction of VanB resistance.
Because teicoplanin and vancomycin are the last line of defense for many bacterial infections, the emergence of resistance to glycopeptide antibiotics in enterococci and streptococci has aroused concern. Despite their similarity in terms of structure and mechanism of action, vancomycin induces the expression of genes that leads to bacterial resistance, and teicoplanin does not. We have used a combination of chemical and enzymatic methods to produce sets of vancomycin and teicoplanin analogues that allow us to consider whether the aglycon, the carbohydrate, or other parts of these molecules stimulate VanB resistance. We show that the teicoplanin and vancomycin aglycons are the structural elements that lead to induction of resistance. We think that lipid-containing analogues of vancomycin, like teicoplanin itself, circumvent resistance because the lipid chain changes the periplasmic distribution of the glycopeptide and, therefore, changes the biosynthetic step that it blocks.


A Bayesian interval dose-finding design addressingOckham's razor: mTPI-2.
There has been an increasing interest in using interval-based Bayesian designs for dose finding, one of which is the modified toxicity probability interval (mTPI) method. We show that the decision rules in mTPI correspond to an optimal rule under a formal Bayesian decision theoretic framework. However, the probability models in mTPI are overly sharpened by the Ockham's razor, which, while in general helps with parsimonious statistical inference, leads to undesirable decisions from safety perspective. We propose a new framework that blunts the Ockham's razor, and demonstrate the superior performance of the new method, called mTPI-2. An online web tool is provided for users who can generate the design, conduct clinical trials, and examine operating characteristics of the designs.


Categorical variables with many categories are preferentially selected in bootstrap-based model selection procedures for multivariable regression models.
Automated variable selection procedures, such as backward elimination, are commonly employed to perform model selection in the context of multivariable regression. The stability of such procedures can be investigated using a bootstrap-based approach. The idea is to apply the variable selection procedure on a large number of bootstrap samples successively and to examine the obtained models, for instance, in terms of the inclusion of specific predictor variables. In this paper, we aim to investigate a particular important problem affecting this method in the case of categorical predictor variables with different numbers of categories and to give recommendations on how to avoid it. For this purpose, we systematically assess the behavior of automated variable selection based on the likelihood ratio test using either bootstrap samples drawn with replacement or subsamples drawn without replacement from the original dataset. Our study consists of extensive simulations and a real data example from the NHANES study. Our main result is that if automated variable selection is conducted on bootstrap samples, variables with more categories are substantially favored over variables with fewer categories and over metric variables even if none of them have any effect. Importantly, variables with no effect and many categories may be (wrongly) preferred to variables with an effect but few categories. We suggest the use of subsamples instead of bootstrap samples to bypass these drawbacks.


[A clinical and pathological study of cerebellar medulloblastoma in adult patients].
In order to study the clinicopathological characteristics, histogenesis and prognosis of medulloblastoma in the adult patients. Altogether 27 patients of medulloblastoma admitted form 1974-1995 were reviewed. In all of the cases, age ranged from 16 to 55, (average 25.8 years) with 21 tumors localized in the cerebellar vermis, and 6 tumors in the cerebellum. Among them, 12 cases were completely while 14 cases were subtotally removed and biopsy was done in only one case. In the 21 patients to be followed up, 7 survived for 2.5-17 years after the operation, and 14 died. The average survival period was 41.6 months. One year survival rate was 71.4%, five years and ten years survival rates were 14.3% respectively. Regarding to the histological types, 14 cases were considered to be classic and 13 cases were desmoplastic by histological classification. Medulloblastoma keeps still the ability of differentiation to neurons and astrocytes confirmed by electronmicroscopy and immunohistochemical staining for Syn, NSE and GFAP. Factors considered responsible to the prognosis included age, tumor location, various therapeutic measurements and the histological classification.