bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast
Authors: Amenta Peter S , Hadad Salim , Lee Maria T , Barnard Nicola , Li Deqin , Myers Jeanne C
Published: February 2003

Ductal and lobular carcinomas comprise most malignancies of the female breast and the morbidity and mortality associated with breast cancer. During the progression from in situ to invasive stages, tumour cells penetrate the epithelial and vascular basement membranes (BM) to realize full metastatic potential. While the definition of these structures has primarily resulted from analysis of laminin and type IV collagen, characterization of newly discovered BM/BM zone (BMZ) proteins will further elucidate the interactions between tumour cells and the host stroma. We have studied the expression of two non‐fibrillar BMZ collagens, the type XV proteoglycan and collagen XIX, in breast cancer where a linear, well‐formed BM becomes fragmented and even lost in the progression of epithelial malignancy. In the normal breast, types XV and XIX were found in all BMZ: epithelial, muscle, neural, endothelial, and fat. In in situ lesions, these two collagens, and particularly type XV, were often absent from the BM/BMZ displaying a continuous or just focally disrupted type IV/laminin staining pattern. In contrast, infiltrating ductal carcinomas showed only rare traces of laminin and collagen IV reactivity adjacent to the glands and tumour nests, and similarly there was little if any evidence of types XV and XIX collagen. All four molecules were, however, detected in the interstitium associated with some of the invasive carcinomas. The data suggest that types XV and XIX collagen are lost early in the development of invasive tumours, prior to penetration and eventual dissolution of the epithelial BM. Disappearance of these proteins from the BM/BMZ may signal remodelling of the extracellular matrix to promote tumour cell infiltration. Copyright © 2003 John Wiley & Sons, Ltd.
Conversion from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine is safe and cost-effective in patients receiving long-term prophylaxis to prevent hepatitis B recurrence after liver transplantation
Authors: Han Steven-Huy , Martin Paul , Edelstein Marc , Hu Rena , Kunder Gregg , Holt Curtis , Saab Sammy , Durazo Francisco , Goldstein Leonard , Farmer Douglas , Ghobrial Rafik M. , Busuttil Ronald W.
Published: February 2003

Recurrent hepatitis B infection after liver transplantation was previously frequent and associated with significant allograft failure and mortality. Recurrence rates of hepatitis B were improved with the use of passive immunoprophylaxis with hepatitis B immune globulin, and later, lamivudine monotherapy. Combination prophylaxis with intravenous hepatitis B immune globulin and lamivudine substantially decreased rates of hepatitis B recurrence, but intravenous administration of hepatitis B immune globulin was expensive and associated with significant adverse effects. In the current study, 59 patients receiving primary liver transplantation for chronic hepatitis B infection were prospectively followed up after converting from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine. All patients tolerated intramuscular hepatitis B immune globulin well. At a median follow-up of 511 days after conversion to intramuscular hepatitis B immune globulin, 58 of 59 patients (98.3%) were hepatitis B surface antigen-negative. Twenty-one patients (35.6%) required a median of one supplemental intravenous hepatitis B immune globulin infusion to maintain therapeutic antibody levels. Economic analysis showed an average cost-effectiveness ratio for combination intramuscular hepatitis B immune globulin plus lamivudine of $52,600 per recurrence prevented, which was far below the cost of lamivudine monotherapy and of intravenous hepatitis B immune globulin alone or in combination with lamivudine. These results suggest that intramuscular administration of hepatitis B immune globulin in combination with lamivudine offers a safe, effective, and cost-effective approach to preventing hepatitis B recurrence after orthotopic liver transplantation.
Successful treatment of fibrosing cholestatic hepatitis using adefovir dipivoxil in a patient with cirrhosis and renal insufficiency
Authors: Tillmann Hans L. , Bock Thomas C. , Bleck Jörg S. , Rosenau Jens , Böker Klaus H. W. , Barg-Hock Hannelore , Becker Thomas , Trautwein Christian , Klempnauer Jürgen , Flemming Peer , Manns Michael P.
Published: February 2003

Fibrosing cholestatic hepatitis is a deleterious manifestation of hepatitis B virus infection in immunocompromised patients. Without treatment, this condition is usually fatal within weeks of onset. Liver retransplantation has not been successfully performed to date, and treatment intervention was generally unsuccessful before the advent of adefovir dipivoxil. However, concerns have been expressed about the use of this agent in patients who are renally compromised. A 40-year-old liver transplant recipient with hepatitis B virus reinfection, resistance to lamivudine, and fibrosing cholestatic hepatitis complicated by terminal renal impairment and spontaneous bacterial peritonitis was treated with adefovir dipivoxil 10 mg after every dialysis. Since initiating treatment with adefovir dipivoxil 10 mg, a dramatic virologic and clinical improvement was observed in this patient. The patient returned to work full-time within 6 months of starting adefovir dipivoxil without the need for liver retransplantation. Serum HBV DNA (Amplicor HBV; Roche Diagnostics, Basle, Switzerland) decreased by 6 log10 copies/mL and became negative (< 400 copies/mL) within 8 weeks of treatment and remains negative at the last available assessment. The patient continues to require renal dialysis, but is generally well. Creatinine clearance improved from 8 mL/min to 16 mL/min during the course of treatment. No adverse events related to adefovir dipivoxil were observed. Adefovir dipivoxil resulted in significant clinical improvement in this patient with hepatitis B virus-induced fibrosing cholestatic hepatitis, despite the presence of renal impairment and lamivudine resistance
Toward better outcomes with tacrolimus therapy: Population pharmacokinetics and individualized dosage prediction in adult liver transplantation
Authors: Staatz Christine E. , Willis Charlene , Taylor Paul J. , Lynch Stephen V. , Tett Susan E.
Published: February 2003

Patient outcomes in transplantation would improve if dosing of immunosuppressive agents was individualized. The aim of this study is to develop a population pharmacokinetic model of tacrolimus in adult liver transplant recipients and test this model in individualizing therapy. Population analysis was performed on data from 68 patients. Estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F) using the nonlinear mixed effects model program (NONMEM). Factors screened for influence on these parameters were weight, age, sex, transplant type, biliary reconstructive procedure, postoperative day, days of therapy, liver function test results, creatinine clearance, hematocrit, corticosteroid dose, and interacting drugs. The predictive performance of the developed model was evaluated through Bayesian forecasting in an independent cohort of 36 patients. No linear correlation existed between tacrolimus dosage and trough concentration (r2
= 0.005). Mean individual Bayesian estimates for CL/F and V/F were 26.5 ± 8.2 (SD) L/hr and 399 ± 185 L, respectively. CL/F was greater in patients with normal liver function. V/F increased with patient weight. CL/F decreased with increasing hematocrit. Based on the derived model, a 70-kg patient with an aspartate aminotransferase (AST) level less than 70 U/L would require a tacrolimus dose of 4.7 mg twice daily to achieve a steady-state trough concentration of 10 ng/mL. A 50-kg patient with an AST level greater than 70 U/L would require a dose of 2.6 mg. Marked interindividual variability (43% to 93%) and residual random error (3.3 ng/mL) were observed. Predictions made using the final model were reasonably nonbiased (0.56 ng/mL), but imprecise (4.8 ng/mL). Pharmacokinetic information obtained will assist in tacrolimus dosing; however, further investigation into reasons for the pharmacokinetic variability of tacrolimus is required.
Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients
Authors: Nair Satheesh , Eason James , Loss George
Published: February 2003

Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (CIs). The aim of this study is to determine whether there is improvement in renal function in liver transplant recipients after switching to sirolimus-based immunosuppression. In this retrospective review, patients who were more than 3 years posttransplantation were selected. Patients who had proteinuria (protein > 300 mg/24 hr), those administered any other nephrotoxic agents, and those with a creatinine clearance (CCr) less than 20 mL/min were excluded. Renal insufficiency was defined as mild (CCr > 70 mL/min), moderate (CCr, 40 to 70 mL/min), or severe (CCr, 20 to 40 mL/min). In the 16 patients studied; there was significant improvement in serum blood urea nitrogen 36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P = .002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P = .001) 6 months after switching to sirolimus therapy. There also was a trend in improvement in CCr from 43 mL min (range, 24 to 68 mL/min) to 49 mL/min (range, 22 to 152 mL/min). Among 9 patients with moderate renal insufficiency, 2 patients improved to mild renal insufficiency, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency. Among 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency, 4 patients improved to moderate renal insufficiency, and 2 patients remained unchanged. No patient developed cellular rejection or other graft-related complications. In liver transplant recipients with chronic renal insufficiency, conversion to sirolimus-based immunosuppression allows complete withdrawal of CIs, leading to some improvement in renal function.
A correlation between the pretransplantation MELD score and mortality in the first two years after liver transplantation
Authors: Onaca Nicholas N. , Levy Marlon F. , Sanchez Edmund Q. , Chinnakotla Srinath , Fasola Carlos G. , Thomas Mark J. , Weinstein Jeffrey S. , Murray Natalie G. , Goldstein Robert M. , Klintmalm Goran B.
Published: February 2003

The Model for End-Stage Liver Disease (MELD) score is now the criteria for allocation in liver transplantation for patients with chronic disease. Although the score has been effective in the prediction of mortality in patients awaiting liver transplantation, its abilities to predict posttransplantation outcome need study. The aim of this study is to compare outcome in the first 2 years after liver transplantation according to the pretransplantation MELD score. The study includes 669 consecutive patients who underwent primary liver transplantation between December 1993 and October 1999 in a single transplant center. Patients who died of malignancy were excluded from the series. Pretransplantation MELD score was calculated using the United Network for Organ Sharing formula. Patients were stratified according to MELD score less than 15, 15 to 24, and 25 and higher. Posttransplantation survival at 3, 6, 12, 18, and 24 months was significantly lower in the groups with a higher MELD score. The difference was significant for hepatitis C and noncholestatic liver diseases, but not cholestatic diseases. In patients with a MELD score between 15 and 24, survival was significantly greater with cholestatic diseases and lower in patients with hepatitis C. In our study, pretransplantation MELD score correlates with survival in the first 2 years after transplantation. There is a survival advantage for patients with cholestatic diseases compared with those with hepatitis C. These findings suggest the need to readjust MELD score-based allocation decisions to consider patient outcome
Predominance of pre-S1 mutated hepatitis B virus in a patient following treatment with adefovir dipivoxil
Authors: Villa Erica , Boarino Valentina , Grottola Antonella , Gelmini Roberta , Lama Nicole G.
Published: February 2003

A liver transplant recipient reinfected with a lamivudine-resistant mixed wild-type/pre-S1-deleted hepatitis B virus (HBV) strain and rescued with adefovir dipivoxil was still HBV DNA positive after more than 1 year of therapy. Analysis of serum HBV DNA, amplified by polymerase chain reaction and directly sequenced by dideoxy nucleotide chain-termination method, showed that adefovir inhibited the wild type, but not the pre-S1-deleted HBV. Predominance of the pre-S1-deleted strain over wild type after adefovir treatment suggests that either adefovir inhibited the wild type more effectively or the pre-S1 mutant replicates more efficiently. The normality of liver condition confirms that to exert its pathogenic effect, the pre-S1-deleted strain requires the presence of wild-type virus
A rational approach for selection of optimal covariate‐based dosing strategies
Authors: Jönsson Siv , Karlsson Mats O.
Published: February 2003

Background

At present, there is no rational approach for choosing a dosing strategy for individualization based on a covariate. An approach to use in establishment of an a priori dosing strategy for individualization is presented. Factors influencing the choice of such a dosing strategy are identified.

Methods

The approach requires definition of the following: target variable, seriousness of deviations from the target (ie, risk function), population model, covariate distributions, and constraints. Minimizing the total risk yields an optimal dosing strategy, estimated as dose sizes for different subpopulations and covariate cutoff values at which doses are incremented or decremented. The method was illustrated with the use of simulated and real drug examples for the situation in which clearance is related to creatinine clearance.

Results

The estimated optimal cutoff(s) paralleled the median creatinine clearance in the population. The extent of variability in clearance explained by creatinine clearance was the main factor influencing the optimal ratios between adjacent dose sizes. An optimal dosing strategy was possible to estimate for the real drug.

Conclusions

The method is simple to perform, although one difficulty lies in defining the target variable and risk function. Our results imply that commonly used constraints in dosing strategies based on renal function (ie, dose ratio of 2 and predetermined cutoffs) are nonoptimal in the sense we propose. Because an optimal dosing strategy may not be practical to use, the therapeutic cost that would result with any constraint can be assessed by comparison of the outcome after the desired and the optimal strategy.

Clinical Pharmacology & Therapeutics (2003) 73, 7–19; doi: 10.1067/mcp.2003.2
Population pharmacodynamic analysis of octreotide in acromegalic patients
Authors: Comets Emmanuelle , Mentré France , Grass Peter , Kawai Ryosei , Marbach Peter , Vonderscher Jacky
Published: February 2003

Introduction

Octreotide is an octapeptide analog of somatostatin used to normalize growth hormone levels in acromegaly. This article presents a population analysis of the relationship between octreotide and growth hormone concentrations in 94 patients with acromegaly, including 10 patients responding incompletely to subcutaneous treatment (poor responders).

Methods

Growth hormone and octreotide concentrations were recorded hourly over 12‐hour time periods during long‐term subcutaneous treatment. Twelve‐hour profiles were also collected on different days up to 2 months after intramuscular injection of the long‐acting formulation. We modeled the inhibition of growth hormone secretion by octreotide with a direct maximum inhibition model. A joint analysis of both formulations was performed with NONMEM (GloboMax, LLC, Hanover, Md). During model building, we examined the relationships between parameters and demographic covariates or formulations with the use of likelihood ratio tests.

Results

The baseline growth hormone level was higher in poor responders and was best described by a bimodal distribution. The maximum inhibition was common to both formulations and had a mean of 90%, with low interindividual variability. Sensitivity to octreotide (50% inhibitory concentration) was found to be slightly lower on average with intramuscular administration than with subcutaneous administration.

Conclusion

Given adequate doses of octreotide, in 72% of 94 patients, growth hormone would decrease to levels below 2.5 ng · mL−1, considered to be a desirable target concentration in acromegaly. This study provides a way to identify poor responders during subcutaneous treatment, allowing an early clinical decision to be made to switch nonresponders to alternative therapies.

Clinical Pharmacology & Therapeutics (2003) 73, 95–106; doi: 10.1067/mcp.2003.6
Effects of Gestation on Ovine Fetal and Maternal Angiotensin Receptor Subtypes in the Heart and Major Blood Vessels
Authors: Burrell J. H. , Hegarty B. D. , McMullen J. R. , Lumbers E. R.
Published: February 2003

Previous studies in fetal sheep have concluded that (a) the vascular AT1 angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT1 specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT1 receptors first appear. We measured AT1 and AT2 receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65‐144 days (term ∼150 days), and in hearts and aortae from lambs, and adult pregnant and non‐pregnant ewes. Both AT1 and AT2 receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT2 receptors were found. The proportion of carotid artery and aortic AT1 receptors increased with age, while the proportion of AT2 receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT1 receptors. The highest density of Ang II receptors was found in the fetal heart where the AT2 subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r= ‐0.44, P < 0.02) due to the decrease in the AT2 subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT1 receptors, and we have documented for the first time that the appearance of AT1 receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT1 receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels.
A Comparison of Modelling Techniques used to Characterise Oxygen Uptake Kinetics During the on‐Transient of Exercise
Authors: Bell Christopher , Paterson Donald H. , Kowalchuk John M. , Padilla Javier , Cunningham David A.
Published: February 2003

We compared estimates for the phase 2 time constant (τ) of oxygen uptake (V̇O2) during moderate‐ and heavy‐intensity exercise, and the slow component of V̇O2 during heavy‐intensity exercise using previously published exponential models. Estimates for τ and the slow component were different (P < 0.05) among models. For moderate‐intensity exercise, a two‐component exponential model, or a mono‐exponential model fitted from 20 s to 3 min were best. For heavy‐intensity exercise, a three‐component model fitted throughout the entire 6 min bout of exercise, or a two‐component model fitted from 20 s were best. When the time delays for the two‐ and three‐component models were equal the best statistical fit was obtained; however, this model produced an inappropriately low ΔV̇O2/ΔWR (WR, work rate) for the projected phase 2 steady state, and the estimate of phase 2 τ was shortened compared with other models. The slow component was quantified as the difference between V̇O2 at end‐exercise (6 min) and at 3 min (ΔV̇O2 (6‐3 min); 259 ml min−1), and also using the phase 3 amplitude terms (truncated to end‐exercise) from exponential fits (409‐833 ml min−1). Onset of the slow component was identified by the phase 3 time delay parameter as being of delayed onset ∼2 min (vs. arbitrary 3 min). Using this delay ΔV̇O2 (6‐2 min) was ∼400 ml min−1. Use of valid consistent methods to estimate τ and the slow component in exercise are needed to advance physiological understanding.
Rat Muscle Microvascular PO2 Kinetics During the Exercise Off‐Transient
Authors: McDonough Paul , Behnke Brad J. , Kindig Casey A. , Poole David C.
Published: February 2003

Dependent upon the relative speed of pulmonary oxygen consumption (V̇O2) and blood flow (Q˙) kinetics, the exercise off‐transient may represent a condition of sub‐ or supra‐optimal perfusion. To date, there are no direct measurements of the dynamics of the V̇O2/Q˙ relationship within the muscle at the onset of the work/recovery transition. To address this issue, microvascular PO2 (PO2,m) dynamics were studied in the spinotrapezius muscles of 11 female Sprague‐Dawley rats (weight ∼220 g) during and following electrical stimulation (1 Hz) to assess the adequacy of Q˙ relative to V̇O2 post exercise. The exercise blood flow response (radioactive microspheres: muscle Q˙ increased ∼240%), and post‐exercise arterial blood pH (7.40 ± 0.02) and blood lactate (1.3 ± 0.4 mM l−1) values were consistent with moderate‐intensity exercise. Recovery PO2,m (i.e. off‐transient) rose progressively until baseline values were achieved (Δend‐recovery exercise PO2,m, 14.0 ± 1.9 Torr) and at no time fell below exercising PO2,m. The off‐transient PO2,m was well fitted by a dual exponential model with both fast (τ= 25.4 ± 5.1 s) and slow (τ= 71.2 ± 34.2 s) components. Furthermore, there was a pronounced delay (54.9 ± 10.7 s) before the onset of the slow component. These data, obtained at the muscle microvascular level, support the notion that muscle V̇O2 falls with faster kinetics than muscle Q˙ during the off‐transient, such that PO2,m increases systematically, though biphasically, during recovery.
Milk Prolactin, Feed Volume and Duration Between Feeds in Women Breastfeeding Their Full‐Term Infants Over a 24 h Period
Authors: Cregan Mark D. , Mitoulas Leon R. , Hartmann Peter E.
Published: February 2003

Previous studies have suggested that the uptake of prolactin from the blood into the milk may be restricted when the alveolus is distended with milk. Therefore the aim of this study was to determine the relationship between prolactin in milk and milk production by measuring the concentration of prolactin in samples of fore‐ and hind‐milk as well as the volume of milk removed for each breast, at each breastfeed over a 24 h period. The mean (± S.D.) concentration of prolactin in milk for all women (n = 15) over the 24 h period was 18.5 ± 11.6 μg l−1 (fore‐milk) and 16.8 ± 12.8 μg l−1 (hind‐milk). The variation between women masked small changes within women in the concentration of prolactin in milk over the 24 h period, therefore a prolactin ratio (individual fore‐ or hind‐milk value divided by the mean for all fore‐ or hind‐milk samples collected over a 24 h period) was determined. The concentration of prolactin was highest in milk between 02.01 and 06.00 h (prolactin ratio for fore‐ to hind‐milk, 1.5), and lowest between 10.01 and 18.00 h (prolactin ratio for fore‐ to hind‐milk, 0.8). Furthermore, we observed that the difference in prolactin concentration between the fore‐ and hind‐milk (fore‐hind gradient) was greatest between 06.01 and 10.00 h (4 μg l−1). To ensure that this effect was not due to permeability in the paracellular pathway, the concentrations of serum albumin and sodium in milk were measured. No significant (P > 0.05) changes over the 24 h period, or with increasing time since last feed were observed. We therefore concluded that when the breast is most drained of milk (in the late evening), and the rate of milk synthesis is greatest, the fore‐hind prolactin gradient in the milk of the following feed (in the early morning) is highest. This is consistent with the observation that prolactin uptake from the blood by the lactocyte is dependent on the fullness of the breast, such that prolactin uptake may be inhibited in full alveoli.
Hypertension‐Related Intermyocyte Junction Remodelling is Associated with a Higher Incidence of Low‐K+‐Induced Lethal Arrhythmias in Isolated Rat Heart
Authors: Tribulova N. , Okruhlicova L. , Novakova S. , Pancza D. , Bernatova I. , Pechanova O. , Weismann P. , Manoach M. , Seki S. , Mochizuki S.
Published: February 2003

The aim of this study was to characterise the arrhythmogenic mechanisms involved in hypokalaemia‐induced sustained ventricular fibrillation (SVF), in hypertensive rats. The hearts from rats with hypertension induced by the nitric oxide synthase inhibitor L‐NAME, and age‐matched normotensive controls, were perfused in Langendorff mode with oxygenated Krebs‐Henseleit solution followed by a K+‐deficient solution. In additional experiments, free intracellular Ca2+ concentration ([Ca2+]i) was measured using fura‐2 in conjunction with an epicardial optical probe. The epicardial electrocardiogram was continuously monitored during all experiments. The gap junction protein connexin‐43 and the ultrastructure of the cardiomyocytes were examined, and selected enzyme activities were measured in situ. There was a higher incidence of low‐K+‐induced SVF in the hearts of hypertensive compared to normotensive rats (83% vs. 33%, P < 0.05). Perfusion with a low‐K+‐containing solution lead to elevation of diastolic [Ca2+]i that was accompanied by premature beats, bigeminy, ventricular tachycardia and transient ventricular fibrillation. These events occurred earlier with increased incidence and duration in the hearts of hypertensive rats (arrhythmia scores: hypertensive, 4.9 ± 0.7; normotensive, 3.1 ± 0.1; P < 0.05), which exhibited apparent remodelling accompanied by a significant decrease in the density of connexin‐43‐positive gap junctions. Moreover, low‐K+‐related myocardial changes, including local impairment of intermyocyte junctions, ultrastructural alterations due to Ca2+ overload and intercellular uncoupling, and decreased enzyme activities were more pronounced and more dispersed in hypertensive than normotensive rats. In conclusion, nitric oxide‐deficient hypertension is associated with decreased myocardial coupling at gap junctions. The further localised deterioration of junctional coupling, due to low‐K+‐induced Ca2+ disturbances, as well as spatial heterogeneity of myocardial alterations including interstitial fibrosis, probably provide the mechanisms for re‐entry and sustaining ventricular fibrillation.
The Nucleus of the Solitary Tract: An Integrating Station for Nociceptive and Cardiorespiratory Afferents
Authors: Boscan Pedro , Pickering Anthony E. , Paton Julian F. R.
Published: February 2003

Painful stimuli can evoke dramatic responses in the cardiovascular and respiratory systems. We have assessed the role of both the sympathetic and parasympathetic nervous system in mediating the reflex tachycardia that accompanies somatic nociception. We describe a major role for the nucleus tractus solitarii (NTS) as a site for integrating nociceptive and cardiorespiratory afferents. Since cardiorespiratory and nociceptive afferents terminate in the NTS, this nucleus offers a powerful opportunity for central modulation. We show that the NTS plays a major role in mediating the reflex tachycardia evoked by somatic noxious stimulation. Similar noxious stimulation attenuates the cardiac component of the peripheral chemoreceptor reflex and inhibits the peripheral chemoreceptor‐evoked excitatory synaptic response of some NTS neurones. The functional interpretation we propose is that by depressing homeostatic reflexes at the NTS, noxious stimulation‐evoked cardiorespiratory changes can be expressed and maintained, which may be essential for the survival of the animal.
The Effects of Steroid Hormones on the Transcription of Genes Encoding Enzymes of Oxidative Phosphorylation
Authors: Scheller Klaus , Sekeris Constantine E.
Published: February 2003

Regulation of energy metabolism is one of the major functions of steroid hormones. In this process, mitochondria, by way of oxidative phosphorylation, play a central role. Depending on the energy needs of the cell, on the tissue, on the developmental stage and on the intensity of the hormonal stimulus, the response can be an activation of pre‐existing respiratory chain components, an increased transcription of nuclear‐encoded and/or mitochondrial‐encoded respiratory chain enzyme (OXPHOS) genes and of biosynthesis of the respective enzyme subunits or, in extreme cases of high energy needs, an increase in the number of mitochondria and mitochondrial DNA content per cell. Some of the hormonally regulated systems involving effects on nuclear and mitochondrial OXPHOS genes are reviewed in this paper. The possible molecular mechanisms of steroid hormone action on nuclear and mitochondrial gene transcription and possible ways of coordination of transcription in these two separate cell compartments involving direct interaction of steroid receptors with hormone response elements in nuclear OXPHOS genes and in mitochondria and induction/activation of nuclear‐encoded regulatory factors affecting mitochondrial gene transcription are presented.
Cold‐Induced Recruitment of Brown Adipose Tissue Thermogenesis
Authors: Klingenspor Martin
Published: February 2003

Non‐shivering thermogenesis in brown adipose tissue is the main mechanism for thermoregulatory heat production in small mammals and newborns. During cold acclimation the sympathetic innervation triggers the recruitment of brown adipose tissue by hyperplasia, which involves the proliferation and differentiation of precursor cells, and by hypertrophy of mature brown adipocytes. Mitochondrial biogenesis and increased synthesis of the uncoupling protein 1 (UCP‐1) are hallmarks of the thermogenic recruitment process. The severalfold increase of mitochondrial protein content during cold acclimation recruits a large capacity for oxidative phosphorylation. However, UCP‐1 increases proton leakage across the inner membrane of brown adipocyte mitochondria and thereby dissipates proton motive force as heat instead of ATP synthesis. During recent years considerable progress has been achieved in the analysis of transcriptional mechanisms controlling Ucp1 gene expression. However, so far only little is known about the molecular basis of cold‐induced mitochondrial biogenesis in brown adipose tissue.
Cdc24, the GDP-GTP Exchange Factor for Cdc42, Is Required for Invasive Hyphal Growth of
Candida albicans
Authors: Bassilana Martine , Blyth James , Arkowitz Robert A.
Published: February 2003

Candida albicans
, the most common human fungal pathogen, is particularly problematic for immunocompromised individuals. The reversible transition of this fungal pathogen to a filamentous form that invades host tissue is important for its virulence. Although different signaling pathways such as a mitogen-activated protein kinase and a protein kinase A cascade are critical for this morphological transition, the function of polarity establishment proteins in this process has not been determined. We examined the role of four different polarity establishment proteins in
C. albicans
invasive growth and virulence by using strains in which one copy of each gene was deleted and the other copy expressed behind the regulatable promoter
MET3
. Strikingly, mutants with ectopic expression of either the Rho G-protein Cdc42 or its exchange factor Cdc24 are unable to form invasive hyphal filaments and germ tubes in response to serum or elevated temperature and yet grow normally as a budding yeast. Furthermore, these mutants are avirulent in a mouse model for systemic infection. This function of the Cdc42 GTPase module is not simply a general feature of polarity establishment proteins. Mutants with ectopic expression of the SH3 domain containing protein Bem1 or the Ras-like G-protein Bud1 can grow in an invasive fashion and are virulent in mice, albeit with reduced efficiency. These results indicate that a specific regulation of Cdc24/Cdc42 activity is required for invasive hyphal growth and suggest that these proteins are required for pathogenicity of
C. albicans.
Microfabrication of ceramics by rapid prototyping process chains
Authors: Knitter R , Bauer W , Göhring D
Published: February 2003

Most shaping processes for ceramics are based on a powder technological moulding process using a negative mould and subsequent thermal compaction. Especially for prototypes and small-lot series of microcomponents, the outlay for moulds is the major costing factor. Therefore the use of rapid prototyping (RP) processes can decisively reduce the costs and time in product development of ceramic microcomponents. By combining the high resolution of, for example, stereolithography as an inexpensive and fast supply for master models with the high flexibility of low-pressure injection moulding, a rapid prototyping process chain (RPPC) has been established for the fabrication of micropatterned ceramic components as functional models or pre-production lots. This RPPC proved to have a very high moulding precision and accuracy in the submillimetre range, but also enables the fabrication of components with outer dimensions of several centimetres. Different RP techniques were investigated with regard to their suitability to be used as master models in the replication chain. The quality of the master models turned out to be of decisive significance for the quality and reproducibility of the ceramic mouldings.
Rapid tooling using plasma spraying and rapid prototyping
Authors: Shan Z , Yan Y , Zhang R , Qi F
Published: February 2003

In the race to fabricate a product to market with increases in speed, cost and quality, the drive to economically decrease tooling lead times becomes more important. Rapid tooling (RT) fabricated at Tsinghua University uses a metal plasma spraying process and rapid prototyping (RP) to form a metal tool. The process uses plasma spraying as the heat pool to melt metal powder and then deposit molten metal on to the substrate made by RP. It provides a quick, accurate, simple and relatively cost effective route for producing metal parts or tools, especially for large tools. The process and key technologies are analysed and described in detail. Applications illustrate that the total costs and lead times for new products can be reduced.
Formation of Fe—Cu metal parts using direct laser sintering
Authors: Zhu H H , Fuh J Y H , Lu L
Published: February 2003

The direct laser sintering process is currently being used to manufacture metallic parts for prototyping and tooling directly. This paper reports on the direct laser sintering of Fe—Cu metal powder using a 200 W CO2 laser. The effects of the ratio of Fe to Cu, the scan speed and atmosphere on the distortion, surface morphology and surface roughness have been investigated. The experiment also investigated the role of adding W particles to the Fe—Cu mixture. The result shows that adding W particles can reduce part distortion. To find the effect of gas protection in laser sintering, the three-dimensional specimens fabricated in both air and N2 atmosphere are also compared.
Crystallographic report: 1,4‐Bis[bis(trimethylsilyl)methyl‐dichlorostannylmethyldimethylsilyl]benzene, p‐{[(Me3Si)2CH]Sn(Cl)2CH2SiMe2}2C6H4
Authors: Dakternieks Dainis , Zobel Bernhard , Tiekink Edward R. T.
Published: January 2003

The dinuclear molecule of p‐{[(Me3Si)2CH]Sn(Cl)2CH2SiMe2}2C6H4 is centrosymmetric and adopts an ‘S’ conformation that is stabilized by intramolecular CH···π interactions. The tin atom exists within a distorted tetrahedron defined by a C2Cl2 donor set. Copyright © 2002 John Wiley & Sons, Ltd.
tert‐Butoxysilanols as model compounds for labile key intermediates of the sol–gel process: crystal and molecular structures of (t‐BuO)3SiOH and HO[(t‐BuO)2SiO]2H
Authors: Beckmann Jens , Dakternieks Dainis , Duthie Andrew , Larchin Megan L. , Tiekink Edward R. T.
Published: January 2003

The tert‐butoxychlorosilanes (t‐BuO)3SiCl (1), (t‐BuO)2SiCl2 (2), and [(t‐BuO)2SiCl]2O (3) were prepared by the reaction of SiCl4 or (Cl3Si)2O with t‐BuOK. Subsequent hydrolysis afforded the tert‐butoxysilanols (t‐BuO)3SiOH (4), (t‐BuO)2Si(OH)2 (5), HO[(t‐BuO)2SiO]2H (6) in high yields. The controlled condensation of 2 and 5 provided HO[(t‐BuO)2SiO]3H (7) in reasonable yields. The tendency of 4–7 to undergo self‐condensation is small, thus enabling their characterization in solution and in the solid state by 29Si NMR spectroscopy, IR spectroscopy and electrospray mass spectrometry, and in the case of 4 and 6 also by X‐ray diffraction. The key feature of the crystal structures is the incorporation of tert‐butoxy groups into the hydrogen bonding. The results obtained are discussed in relation to the sol–gel process. Copyright © 2002 John Wiley & Sons, Ltd.
Synthesis and characterization of novel chelated dimethylamino lithium alkoxides: molecular structures of [1‐LiOC(C6H11)2‐2‐NMe2C6H4]2 and [1‐LiOCPh2CH2‐2‐NMe2C6H4]2
Authors: Al‐Masri Harbi Tomah , Sieler Joachim , Hey‐Hawkins Evamarie
Published: January 2003

From the reaction of 1‐HOCPh2‐2‐NMe2C6H4 (1), 1‐HOC(C6H11)2‐2‐NMe2C6H4 (2) and 1‐HOCPh2CH2‐2‐NMe2C6H4 (3) with n‐BuLi in diethyl ether, the solvent‐free chelated dimethylamino lithium alkoxides [1‐LiOCPh2‐2‐NMe2C6H4]2 (4), [1‐LiOC(C6H11)2‐2‐NMe2C6H4]2 (5) and [1‐LiOCPh2CH2‐2‐NMe2C6H4]2 (6) were obtained. The lithium alkoxides 4–6 were characterized by 1H, 7Li, and 13C NMR spectroscopy. Crystal structure determinations of 5 and 6 were carried out. Compounds 5 and 6 are examples of structurally characterized solvent‐free chelated dimethylamino lithium alkoxides and 6 is a rare example of this type containing a seven‐membered ring. Copyright © 2002 John Wiley & Sons, Ltd.
Synthesis of ruthenium complexes with carbonyl and polypyridyl ligands derived from dipyrido[3,2‐a:2′,3′‐c]phenazine: application to the water gas shift reaction
Authors: Aguirre P. , López R. , Villagra D. , Azocar‐Guzman I. , Pardey A. J. , Moya S. A.
Published: January 2003

The preparation and spectroscopic properties of new dipyrido[3,2‐a:2′,3′‐c]phenazine ruthenium complexes are described. The complexes show high catalytic activity in the water gas shift reaction in a basic medium under mild conditions (PCO = 0.9 atm at 100 °C). Copyright © 2002 John Wiley & Sons, Ltd.
Review: Biodegradation of tributyltins (organotins) by marine bacteria
Authors: Dubey S. K. , Roy U.
Published: January 2003

Many marine bacterial strains have an inherent capability to degrade toxic organotin compounds, especially tributyltins (TBTs), that enter into the environment in the form of insecticides, fungicides and antifouling paints as a result of anthropogenic and industrial activities. Significant degradation of these compounds in the ambient environment may take several years, and it is necessary to consider methods or strategies that can accelerate the degradation process. There have been few demonstrations of biological degradation of these organotin biocides exclusively in laboratory‐scale experiments. Compared with the few bench‐scale degradation processes, there are no reports of field‐scale processes for TBT bioremediation, in spite of its serious environmental threat to non‐target organisms in the aquatic environment. Implementation of field‐scale biodegradation of TBT requires inputs from biology, hydrology, geology, chemistry and civil engineering. A framework is emerging that can be adapted to develop new processes for bioremediation of toxic environmental wastes. In the case of TBT bioremediation, this framework incorporates screening and identification of natural bacterial strains, determination of optimal conditions for growth of isolates and TBT degradation, establishment of new metabolic pathways involved in TBT degradation, identification, localization and cloning of genes involved in degradation and in TBT resistance, development of suitable microbial strains using genetic manipulation techniques for practical applications and optimization of practical engineering processes for bioremediation of organotin‐contaminated sites. The present review mainly addresses the aspect of TBT biodegradation with special reference to environmental sources of TBT, chemical structure and biological activity, resistant and degrading bacterial strains, possible mechanisms of resistance and degradation and the genetic and biochemical basis of TBT degradation and resistance. It also evaluates the feasibility and potential of natural and genetically modified TBT‐degrading bacterial strains in field‐scale experiments to bioremediate TBT‐contaminated marine sites, and makes recommendations for more intensive and focused research in the area of TBT bioremediation mediated by marine bacterial strains. Copyright © 2002 John Wiley & Sons, Ltd.
Preparation and characterization of monodisperse magnetic poly(styrene butyl acrylate methacrylic acid) microspheres in the presence of a polar solvent
Authors: Xie Gang , Zhang Qiuyu , Luo Zhengping , Wu Min , Li Tiehu
Published: January 2003

Magnetic poly(styrene butyl acrylate methacrylic acid) [P(St–BA–MAA)] microspheres were prepared by emulsifier‐free emulsion polymerization in the presence of a polar solvent and a ferrofluid prepared by a coprecipitation method. The effects of some polymerization parameters, such as the medium polarity, reaction temperature, initiator content, and surfactant content in the ferrofluid, on the particle diameter and particle size distribution of magnetic P(St–BA–MAA) microspheres were examined in detail. The results showed that the electrostatic repulsion in the polymerization system significantly affected the monodispersity of the resulting magnetic polymer microspheres. The proper electrostatic repulsion, achieved through changes in the medium polarity and amount of surfactant in the polymerization system, improved the monodispersity, but a higher or lower repulsion led to a decrease in the monodispersity. Although the existence of surfactant and magnetite particles reduced the monodispersity more or less, the polymerization behavior of an emulsifier‐free emulsion polymerization in the presence of the ferrofluid was analogous to that of a conventional emulsifier‐free emulsion polymerization. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1733–1738, 2003
Synthesis, polymerization, and copolymerization of aliphatic vinyl azide
Authors: James Nirmala R. , Jayakrishnan A.
Published: January 2003

The synthesis and characterization of a fully aliphatic polymeric azide by polymerization of its vinyl monomer 1,3‐diazidoisopropyl methacrylate (DAIPM) is reported. DAIPM was prepared by azidation of epichlorohydrin followed by coupling with methacrylic acid. Homopolymer and copolymers with methyl methacrylate were prepared and characterized by IR, GPC, TGA, DTA, and elemental analyses. These polymers are freely soluble in organic solvents like dichloromethane, tetrahydrofuran, dimethyl formamide, acetone, and so forth and do not crosslink on storing. The polymers show decreased thermal stability with an increase in azide content and undergo exothermic decomposition on heating. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1852–1857, 2003
Synthesis and characterization of ethoxyethyl α‐cyanoacrylate and reaction intermediates
Authors: Hwang Yu‐Haur , Hwang Chi‐Ping , Tsiang Raymond Chien‐Chao , Chen Michael
Published: January 2003

Ethoxyethyl α‐cyanoacrylate was synthesized by first making oligo(ethoxyethyl α‐cyanoacrylate) through a condensation reaction of ethoxyethyl cyanoacetate with paraformaldehyde, followed by a depolymerization of the oligomer at an elevated temperature in an acidic atmosphere with a high vacuum. The ethoxyethyl cyanoacetate was in turn synthesized from an esterification of ethoxyethanol and cyanoacetic acid. The molecular structure of the target monomer and the corresponding intermediates were corroborated by IR and 1H‐NMR. Solvents having a lower polarity led to the formation of oligomers having higher molecular weights. The molecular weight distribution of the oligomer revealed that the reaction of ethoxyethyl cyanoacetate with formaldehyde followed a mechanism comprising monomer activations, anionic reactions, and chain scissions. DSC thermograms demonstrated the cured ethoxyethyl α‐cyanoacrylate was nearly amorphous, containing little or low crystallinity. Mechanical testing data indicated that the cured ethoxyethyl α‐cyanoacrylate was a hard adhesive with higher toughness than the conventional ethyl α‐cyanoacrylate. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1758–1773, 2003
Influence of urethane group on properties of crosslinked polyurethane elastomers
Authors: Ciobanu Constantin , Han Xiaozu , Cascaval Constantin N. , Guo Fengchun , Rosu Dan , Ignat Leonard , Moroi Gabriela
Published: January 2003

Three series of weakly crosslinked polyurethanes based on a hydroxyterminated polybutadiene, hydroxyterminated butadiene–acrylonitrile copolymer, and hydroxyterminated ethylene–adipate–maleate–fumarate copolymer were prepared while varying the hard segment content between 1.72 and 2.36 mol NHCOO/1000 g polymer. Information on the microphase structure and the properties of the synthesized polyurethanes was obtained by differential scanning calorimetry, wide‐angle X‐ray scattering, and mechanical studies. Up to a urethane concentration of around 2 mol NHCOO/1000 g polymer, there is a mixture of hard–hard and hard–soft segments. Above this concentration a large part of the hard–soft segments passes into hard–hard crystallites, liberating the soft segments. The best mechanical properties of the studied polyurethanes were found for a urethane concentration of around 2 mol NHCOO/1000 g polymer. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1858–1867, 2003
Mechanical properties study of photocured paperboard surface treated with aliphatic epoxy diacrylate
Authors: Khan Mubarak A. , Rahman M. Mizanur , Gosh Manik K. , Chowdhury T. A.
Published: January 2003

In order to improve the quality of paperboard (a well‐known packing material) surface by photocuring method, different formulations were developed with aliphatic epoxy diacrylate (EA‐1020) oligomer along with reactive monomers of various functionalities. The reactive monomers are tripropylene glycol diacrylate (TPGDA), a difunctional monomer, and trimethylol propane triacrylate (TMPTA), a trifunctional monomer. 2‐Benzyl‐2‐dimethylamino‐1(4morpholinophenyl) butanone‐1 (Irgacure 369), a photoinitiator (2%), was incorporated into the formulations to initiate photocuring reaction. The formulated solutions were coated on clean glass plate and irradiated under UV radiation of different intensities. Different physical properties like pendulum hardness and gel content of the cured films were studied. The formulation containing TMPTA showed better properties. After characterization of the films, these formulations were applied on paperboard surfaces and cured under the same UV radiation. Various physicomechanical properties such as pendulum hardness, tensile properties, surface gloss, adhesion, abrasion, and water uptake were studied. The best performance was obtained at 12 passes of radiation with 18% TMPTA‐containing formulation. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1774–1780, 2003