bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional TRPV4 channels are expressed in human airway smooth muscle cells
Authors: Jia Yanlin , Wang Xin , Varty LoriAnn , Rizzo Charles A. , Yang Richard , Correll Craig C. , Phelps P. Tara , Egan Robert W. , Hey John A.
Published: April 2004

Hypotonic stimulation induces airway constriction in normal and asthmatic airways. However, the osmolarity sensor in the airway has not been characterized. TRPV4 (also known as VR-OAC, VRL-2, TRP12, OTRPC4), an osmotic-sensitive cation channel in the transient receptor potential (TRP) channel family, was recently cloned. In the present study, we show that TRPV4 mRNA was expressed in cultured human airway smooth muscle cells as analyzed by RT-PCR. Hypotonic stimulation induced Ca2+influx in human airway smooth muscle cells in an osmolarity-dependent manner, consistent with the reported biological activity of TRPV4 in transfected cells. In cultured muscle cells, 4α-phorbol 12,13-didecanoate (4-αPDD), a TRPV4 ligand, increased intracellular Ca2+level only when Ca2+was present in the extracellular solution. The 4-αPDD-induced Ca2+response was inhibited by ruthenium red (1 μM), a known TRPV4 inhibitor, but not by capsazepine (1 μM), a TRPV1 antagonist, indicating that 4-αPDD-induced Ca2+response is mediated by TRPV4. Verapamil (10 μM), an L-type voltage-gated Ca2+channel inhibitor, had no effect on the 4-αPDD-induced Ca2+response, excluding the involvement of L-type Ca2+channels. Furthermore, hypotonic stimulation elicited smooth muscle contraction through a mechanism dependent on membrane Ca2+channels in both isolated human and guinea pig airways. Hypotonicity-induced airway contraction was not inhibited by the L-type Ca2+channel inhibitor nifedipine (1 μM) or by the TRPV1 inhibitor capsazepine (1 μM). We conclude that functional TRPV4 is expressed in human airway smooth muscle cells and may act as an osmolarity sensor in the airway.
Matrix metalloproteinase-2 and -9 expression increases inMycoplasma-infected airways but is not required for microvascular remodeling
Authors: Baluk Peter , Raymond Wilfred W. , Ator Erin , Coussens Lisa M. , McDonald Donald M. , Caughey George H.
Published: April 2004

Murine Mycoplasma pulmonis infection induces chronic lung and airway inflammation accompanied by profound and persistent microvascular remodeling in tracheobronchial mucosa. Because matrix metalloproteinase (MMP)-2 and -9 are important for angiogenesis associated with placental and long bone development and skin cancer, we hypothesized that they contribute to microvascular remodeling in airways infected with M. pulmonis. To test this hypothesis, we compared microvascular changes in airways after M. pulmonis infection of wild-type FVB/N mice with those of MMP-9−/−and MMP-2−/−/MMP-9−/−double-null mice and mice treated with the broad-spectrum MMP inhibitor AG3340 (Prinomastat). Using zymography and immunohistochemistry, we find that MMP-2 and MMP-9 rise strikingly in lungs and airways of infected wild-type FVB/N and C57BL/6 mice, with no zymographic activity or immunoreactivity in MMP-2−/−/MMP-9−/−animals. However, microvascular remodeling as assessed by Lycopersicon esculentum lectin staining of whole-mounted tracheae is as severe in infected MMP-9−/−, MMP-2−/−/MMP-9−/−and AG3340-treated mice as in wild-type mice. Furthermore, all groups of infected mice develop similar inflammatory infiltrates and exhibit similar overall disease severity as indicated by decrease in body weight and increase in lung weight. Uninfected wild-type tracheae show negligible MMP-2 immunoreactivity, with scant MMP-9 immunoreactivity in and around growing cartilage. By contrast, MMP-2 appears in epithelial cells of infected, wild-type tracheae, and MMP-9 localizes to a large population of infiltrating leukocytes. We conclude that despite major increases in expression, MMP-2 and MMP-9 are not essential for microvascular remodeling in M. pulmonis-induced chronic airway inflammation.
Surfactant proteins A and D enhance the phagocytosis ofChlamydiainto THP-1 cells
Authors: Oberley Rebecca E. , Ault Kevin A. , Neff Traci L. , Khubchandani Kavita R. , Crouch Erika C. , Snyder Jeanne M.
Published: April 2004

Chlamydiae are intracellular bacterial pathogens that infect mucosal surfaces, i.e., the epithelium of the lung, genital tract, and conjunctiva of the eye, as well as alveolar macrophages. In the present study, we show that pulmonary surfactant protein A (SP-A) and surfactant protein D (SP-D), lung collectins involved in innate host defense, enhance the phagocytosis of Chlamydia pneumoniae and Chlamydia trachomatis by THP-1 cells, a human monocyte/macrophage cell line. We also show that SP-A is able to aggregate both C. trachomatis and C. pneumoniae but that SP-D only aggregates C. pneumoniae. In addition, we found that after phagocytosis in the presence of SP-A, the number of viable C. trachomatis pathogens in the THP-1 cells 48 h later was increased ∼3.5-fold. These findings suggest that SP-A and SP-D interact with chlamydial pathogens and enhance their phagocytosis into macrophages. In addition, the chlamydial pathogens internalized in the presence of collectins are able to grow and replicate in the THP-1 cells after phagocytosis.
Control of oxidative phosphorylation during insect metamorphosis
Authors: Chamberlin M. E.
Published: April 2004

The midgut of the tobacco hornworm ( Manduca sexta) is a highly aerobic tissue that is destroyed and replaced by a pupal epithelium at metamorphosis. To determine how oxidative phosphorylation is altered during the programmed death of the larval cells, top-down control analysis was performed on mitochondria isolated from the midguts of larvae before and after the commitment to pupation. Oxygen consumption and protonmotive force (measured as membrane potential in the presence of nigericin) were monitored to determine the kinetic responses of the substrate oxidation system, proton leak, and phosphorylation system to changes in the membrane potential. Mitochondria from precommitment larvae have higher respiration rates than those from postcommitment larvae. State 4 respiration is controlled by the proton leak and the substrate oxidation system. In state 3, the substrate oxidation system exerted 90% of the control over respiration, and this high level of control did not change with development. Elasticity analysis, however, revealed that, after commitment, the activity of the substrate oxidation system falls. This decline may be due, in part, to a loss of cytochrome c from the mitochondria. There are no differences in the kinetics of the phosphorylation system, indicating that neither the F1F0ATP synthase nor the adenine nucleotide translocase is affected in the early stages of metamorphosis. An increase in proton conductance was observed in mitochondria isolated from postcommitment larvae, indicating that membrane area, lipid composition, or proton-conducting proteins may be altered during the early stages of the programmed cell death of the larval epithelium.
Hemorrhage-induced acute lung injury is TLR-4 dependent
Authors: Barsness Katherine A. , Arcaroli John , Harken Alden H. , Abraham Edward , Banerjee Anirban , Reznikov Leonid , McIntyre Robert C.
Published: April 2004

Toll-like receptor 4 (TLR-4), initially identified as an LPS receptor, is critical to the signaling of a variety of danger signals, including heat shock protein 60, fibrinogen, and fibronectin. Recent data also suggest that TLR-4 plays a role in determining survival in both endotoxemia and hemorrhagic shock. We hypothesized that a functional TLR-4 would be required for hemorrhage and endotoxin-induced acute lung injury. Hemorrhage- and endotoxin-induced lung TNF-α mRNA and protein production, neutrophil accumulation, and protein permeability were dependent on a functional TLR-4. Hemorrhage-induced nuclear factor (NF)-κB activation was independent of functional TLR-4, whereas endotoxin-induced activation of NF-κB requires a functional TLR-4 for full response. Therefore, we conclude that 1) hemorrhage-induced acute lung injury is TLR-4 dependent and 2) hemorrhage has a different and distinct TLR-4-dependent intracellular activation mechanism compared with endotoxemia.
Luminal flow induces eNOS activation and translocation in the rat thick ascending limb
Authors: Ortiz Pablo A. , Hong Nancy J. , Garvin Jeffrey L.
Published: April 2004

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) acts as an autacoid to inhibit NaCl absorption in the thick ascending limb of the loop of Henle (THAL). In the vasculature, shear stress activates eNOS. We hypothesized that increasing luminal flow activates eNOS and enhances NO production in the THAL. We measured NO production by isolated, perfused THALs using a NO-sensitive microelectrode. Increasing luminal flow from 0 to 20 nl/min increased NO production by 43.1 ± 4.1 pA/mm of tubule ( n = 10, P < 0.05), and this response was blunted (92%) by the NOS inhibitor l-ωnitro-methylarginine ( P < 0.05). We studied the effect of flow on eNOS subcellular localization. In the absence of flow, eNOS was diffusely localized throughout the cell (basolateral = 33 ± 4%; middle = 27 ± 3%; apical = 40 ± 4% of total eNOS). Increasing luminal flow induced eNOS translocation to the apical membrane, as evidenced by a 60% increase in eNOS immunoreactivity in the apical membrane (from 40 ± 4 to 65 ± 2%; n = 6; P < 0.05). Disrupting the actin cytoskeleton with cytochalasin D (10 μM) reduced flow-induced NO production by 62% (from 37.1 ± 3.4 to 14.0 ± 2.4 pA/mm tubule, n = 7, P < 0.04) and blocked flow-induced eNOS translocation. Flow also increased the amount of phosphorylated eNOS (Ser1179) at the apical membrane (from 25 ± 2 to 56 ± 2%; P < 0.05). We conclude that increasing luminal flow induces eNOS activation and translocation to the apical membrane in THALs. These are the first data showing that flow regulates eNOS in epithelial cells. This may be an important mechanism for regulation of NO levels in the renal medulla.
Renal dopamine D1receptor dysfunction is acquired and not inherited in obese Zucker rats
Authors: Banday Anees Ahmad , Hussain Tahir , Lokhandwala Mustafa F.
Published: April 2004

In essential hypertension, the defect in renal dopamine (DA) D1receptor function is intrinsic to proximal tubules as this phenomenon is also seen in primary proximal tubule cultures from spontaneously hypertensive rats (SHR) and essential hypertensive patients. Previously, a defect was reported in renal D1receptor function in obese Zucker rats. In the present study, we sought to determine whether this D1receptor dysfunction is intrinsic in these animals. In primary proximal tubular epithelial cells (PTECs) from lean and obese rats, DA inhibited Na-K-ATPase (NKA) activity in PTECs from both groups of rats. Basal NKA activity, D1receptor protein expression, and their coupling to G proteins were similar in cells from both groups. However, when PTECs from lean and obese rats were cultured in 20% serum from obese rats, DA failed to inhibit NKA activity, which was accompanied by a reduction in D1receptor expression and a defect in D1receptor-G protein coupling. No such defects in the inhibitory effect of DA on NKA activity, D1receptor numbers, or coupling were seen when PTECs from both lean and obese rats were grown in 20% serum from lean or rosiglitazone-treated obese (RTO) rats. RTO rat serum had normal blood glucose and reduced plasma levels of insulin compared with serum from obese rats. Furthermore, chronic insulin treatment of PTECs from lean and obese rats caused an attenuation in DA-induced NKA inhibition, a decrease in D1receptor expression, and D1receptor-G protein uncoupling. These results suggest that defective D1receptor function in obese Zucker rats is not inherited but contributed to by hyperinsulinemia and/or other circulating factors associated with obesity.
Exercise training modulates heat shock protein response in diabetic rats
Authors: Atalay Mustafa , Oksala Niku K. J. , Laaksonen David E. , Khanna Savita , Nakao Chitose , Lappalainen Jani , Roy Sashwati , Hänninen Osmo , Sen Chandan K.
Published: April 2004

Strenuous exercise induces oxidative stress and modification of intracellular proteins. Exercise training, however, upregulates endogenous antioxidant defenses and heat shock protein (HSP) expression. In diabetes, perturbations in the endogenous antioxidant and HSP protection have been reported. The aim of this study was to examine the effect of 8 wk of endurance training on HSP expression and oxidative stress markers in the skeletal muscle, heart, and liver of streptozotocin-induced diabetic (SID) and nondiabetic control rats. Induction of diabetes decreased HSP72 expression in heart, liver, and vastus lateralis muscles. SID increased heme oxygenase-1, an oxidative stress-inducible HSP, in liver, red gastrocnemius muscle, and vastus lateralis muscle and glucose-regulated protein 75 in liver. SID increased HSP90 levels in the heart, but levels decreased in the liver. Diabetes induced oxidative stress marker protein carbonyl levels and tissue inflammation. Although endurance training increased the expression of HSP72 in all of the tissues examined, this induction was less pronounced in diabetic rats than in nondiabetic controls. Furthermore, endurance training induced the activation and expression of transcriptional regulator heat shock factor-1 only in nondiabetic control animals. In summary, diabetes may increase susceptibility to oxidative damage and impair HSP protection, but endurance training may offset some of the adverse effects of diabetes by upregulating tissue HSP expression. Our results suggest that diabetes impairs HSP protection, possibly via transcriptionally mediated mechanisms.
Voluntary activation level and muscle fiber recruitment of human quadriceps during lengthening contractions
Authors: Beltman J. G. M. , Sargeant A. J. , van Mechelen W. , de Haan A.
Published: April 2004

Voluntary activation levels during lengthening, isometric, and shortening contractions (angular velocity 60°/s) were investigated by using electrical stimulation of the femoral nerve (triplet, 300 Hz) superimposed on maximal efforts. Recruitment of fiber populations was investigated by using the phosphocreatine-to-creatine ratio (PCr/Cr) of single characterized muscle fibers obtained from needle biopsies at rest and immediately after a series of 10 lengthening, isometric, and shortening contractions (1 s on/1 s off). Maximal voluntary torque was significantly higher during lengthening (270 ± 55 N·m) compared with shortening contractions (199 ± 47 N·m, P < 0.05) but was not different from isometric contractions (252 ± 47 N·m). Isometric torque was higher than torque during shortening ( P < 0.05). Voluntary activation level during maximal attempted lengthening contractions (79 ± 8%) was significantly lower compared with isometric (93 ± 5%) and shortening contractions (92 ± 3%, P < 0.05). Mean PCr/Cr values of all fibers from all subjects at rest were 2.5 ± 0.6, 2.0 ± 0.7, and 2.0 ± 0.7, respectively, for type I, IIa, and IIax fibers. After 10 contractions, the mean PCr/Cr values for grouped fiber populations (regardless of fiber type) were all significantly different from rest (1.3 ± 0.2, 0.7 ± 0.3, and 0.8 ± 0.6 for lengthening, isometric, and shortening contractions, respectively; P < 0.05). The cumulative distributions of individual fiber populations after either contraction mode were significantly different from rest ( P < 0.05). Curves after lengthening contractions were less shifted compared with curves from isometric and shortening contractions ( P < 0.05), with a smaller shift for the type IIax compared with type I fibers in the lengthening contractions. The results indicate a reduced voluntary drive during lengthening contractions. PCr/Cr values of single fibers indicated a hierarchical order of recruitment of all fiber populations during maximal attempted lengthening contractions.
Changes in neutrophil surface receptor expression, degranulation, and respiratory burst activity after moderate- and high-intensity exercise
Authors: Peake Jonathan , Wilson Gary , Hordern Matthew , Suzuki Katsuhiko , Yamaya Kanemitsu , Nosaka Kazunori , Mackinnon Laurel , Coombes Jeff S.
Published: April 2004

Intense exercise stimulates the systemic release of a variety of factors that alter neutrophil surface receptor expression and functional activity. These alterations may influence resistance to infection after intense exercise. The aim of this study was to examine the influence of exercise intensity on neutrophil receptor expression, degranulation (measured by plasma and intracellular myeloperoxidase concentrations), and respiratory burst activity. Ten well-trained male runners ran on a treadmill for 60 min at 60% [moderate-intensity exercise (MI)] and 85% maximal oxygen consumption [high-intensity exercise (HI)]. Blood was drawn immediately before and after exercise and at 1 h postexercise. Immediately after HI, the expression of the neutrophil receptor CD16 was significantly below preexercise values ( P < 0.01), whereas MI significantly reduced CD35 expression below preexercise values ( P < 0.05). One hour after exercise at both intensities, there was a significant decline in CD11b expression ( P < 0.05) and a further decrease in CD16 expression compared with preexercise values ( P < 0.01). CD16 expression was lower 1 h after HI than 1 h after MI ( P < 0.01). Immediately after HI, intracellular myeloperoxidase concentration was less than preexercise values ( P < 0.01), whereas plasma myeloperoxidase concentration was greater ( P < 0.01), indicating that HI stimulated neutrophil degranulation. Plasma myeloperoxidase concentration was higher immediately after HI than after MI ( P < 0.01). Neutrophil respiratory burst activity increased after HI ( P < 0.01). In summary, both MI and HI reduced neutrophil surface receptor expression. Although CD16 expression was reduced to a greater extent after HI, this reduction did not impair neutrophil degranulation and respiratory burst activity.
Temporal Sparseness of the Premotor Drive Is Important for Rapid Learning in a Neural Network Model of Birdsong
Authors: Fiete Ila R. , Hahnloser Richard H.R. , Fee Michale S. , Seung H. Sebastian
Published: April 2004

Sparse neural codes have been widely observed in cortical sensory and motor areas. A striking example of sparse temporal coding is in the song-related premotor area high vocal center (HVC) of songbirds: The motor neurons innervating avian vocal muscles are driven by premotor nucleus robustus archistriatalis (RA), which is in turn driven by nucleus HVC. Recent experiments reveal that RA-projecting HVC neurons fire just one burst per song motif. However, the function of this remarkable temporal sparseness has remained unclear. Because birdsong is a clear example of a learned complex motor behavior, we explore in a neural network model with the help of numerical and analytical techniques the possible role of sparse premotor neural codes in song-related motor learning. In numerical simulations with nonlinear neurons, as HVC activity is made progressively less sparse, the minimum learning time increases significantly. Heuristically, this slowdown arises from increasing interference in the weight updates for different synapses. If activity in HVC is sparse, synaptic interference is reduced, and is minimized if each synapse from HVC to RA is used only once in the motif, which is the situation observed experimentally. Our numerical results are corroborated by a theoretical analysis of learning in linear networks, for which we derive a relationship between sparse activity, synaptic interference, and learning time. If songbirds acquire their songs under significant pressure to learn quickly, this study predicts that HVC activity, currently measured only in adults, should also be sparse during the sensorimotor phase in the juvenile bird. We discuss the relevance of these results, linking sparse codes and learning speed, to other multilayered sensory and motor systems.
Sense of Taste in a New World Monkey, the Common Marmoset. II. Link Between Behavior and Nerve Activity
Authors: Danilova Vicktoria , Hellekant Göran
Published: April 2004

In a previous study, we characterized the gustatory system of a New World monkey the common marmoset, Callithrix jacchus jacchus, with electrophysiological techniques by recording from taste fibers of the chorda tympani proper (CT) and glossopharyngeal (NG) nerves. Hierarchical cluster analysis identified three clusters of taste fibers: S fibers, responding predominantly to sweeteners, Q fibers, responding predominantly to bitter stimuli, and H fibers, responding predominantly to acids. In this study, we employed two behavioral techniques, the two-bottle preference (TBP) and conditioned taste aversion (CTA), to study the taste of the compounds used in the previous electrophysiological study. The results showed that compounds that did not stimulate any taste fibers were neither preferred nor rejected. Compounds that activated only S fibers were always preferred over water. When aversion to sucrose was created by the CTA method, these compounds were rejected. Compounds that activated Q fibers were rejected and consumed less than water. We studied the relationship between intake and net response from S and Q fibers in the CT and NG nerves. Intake was measured as a preference ratio in TBP test. The net response was defined as: (SCT + SNG) − (QCT + QNG), where SCT + SNG denotes the sum of the responses in S fibers of the CT and NG nerves. Similarly, QCT + QNG represents the sum of the responses in Q fibers of the CT and NG nerves. The relationship between intake and the Net response was linear with a Pearson correlation coefficient 0.85. This study supports our hypothesis that intake is influenced by S and Q fibers, where S fibers serve as a hedonically positive input and Q fibers as a hedonically negative input.
Evaluation of the host transcriptional response to human cytomegalovirus infection
Authors: Challacombe Jean F. , Rechtsteiner Andreas , Gottardo Raphael , Rocha Luis M. , Browne Edward P. , Shenk Thomas , Altherr Michael R. , Brettin Thomas S.
Published: April 2004

Gene expression data from human cytomegalovirus (HCMV)-infected cells were analyzed using DNA-Chip Analyzer (dChip) followed by singular value decomposition (SVD) and compared with a previous analysis of the same data that employed GeneChip software and a fold change filtering approach. dChip and SVD analysis revealed two clusters of coexpressed human genes responding differently to HCMV infection: one containing some genes identified previously, and another that was largely unique to this analysis. Annotating these genes, we identified several functional categories important to host cell responses to HCMV infection. These categories included genes involved in transcriptional regulation, oncogenesis, and cell cycle regulation, which were more prevalent in cluster 1, and genes involved in immune system regulation, signal transduction, and cell adhesion, which were more prevalent in cluster 2. Within these categories, we found genes involved in the host response to HCMV infection (mainly in cluster 1), as well as genes targeted by HCMV’s immune evasion strategies (mainly in cluster 2). As the second group of genes identified by the dChip and SVD approach was statistically and biologically significant, our results point out the advantages of using different methods to analyze gene expression data.
Influence of Emergency Room Fee on Acute Stroke Presentation in a Public Hospital in Hong Kong
Authors: Chow Kai Ming , Szeto Cheuk Chun , Hui Andrew Che-Fai , Leung Cecilia Shuk-Fong , Wong Ka Sing
Published: April 2004

A new system of emergency room fee-for-service was recently introduced at public hospitals in Hong Kong. A prospective observational study was undertaken to investigate the effects of the emergency room consultation fee system on presentation delay of acute stroke patients and evaluation of timing of patient presentation with acute stroke. We reviewed 2 specified periods (2-month interval each) before and after the consultation fee system at a public hospital. Primary outcome measures were time from onset of stroke symptoms to arrival at hospital, and predictors of such a time delay. A total of 173 subjects were recruited before institution of the consultation fee system, and 189 after inception of the new system. The mean age was 71 years. The median delay between symptom onset and arrival at hospital was 9 h. Acute ischemic stroke accounted for 91% of the stroke diagnoses. The median baseline NIHSS score measured 6. The median delay for patients before the emergency room consultation fee system was 9.7 h, compared with 8.4 h after introduction of the consultation fee (p = 0.66). At presentation, patients admitted during the consultation fee system were significantly more likely to be unconscious and be in a worse functional premorbid state. We found no difference in the frequency of general practitioner contact between the 2 study periods. Overall, univariate analyses showed that patient age, baseline NIHSS score, consciousness level upon arrival at the emergency department and premorbid ambulatory status were significant factors associated with the timing of presentation after acute stroke. A multivariate linear regression model demonstrated two independent factors: patient age younger than 70 years was independently related to presentation delay, whereas severity of stroke as indicated by unconsciousness upon arrival was associated with shorter delay. While we demonstrated no delays in acute stroke presentation accrued from enactment of the emergency room fee, physicians should endeavor to further explore strategies of reducing the late presentation of acute stroke.
Neuronal Apoptosis in Neurodegenerative Diseases: From Basic Research to Clinical Application
Authors: Kermer Pawel , Liman Jan , Weishaupt Jochen H. , Bähr Mathias
Published: April 2004

In recent years, the investigation of erroneous regulation of apoptotic mechanisms during acute and chronic injury of neuronal cells has gained increasing attention. Besides acute neuronal trauma and ischemia, chronic neurodegenerative diseases like Alzheimer’s, Huntington’s, Parkinson’s and Lou-Gehrig’s disease (amyotrophic lateral sclerosis) are of particular interest. The present article will provide an overview of basic apoptotic mechanisms, the contribution of neuronal apoptosis to the above-mentioned disorders, potential clinical applications and their limitations and the possible implications for future studies regarding these neurodegenerative diseases.
Pharmacological Hyperprolactinemia Attenuates Hydrocortisone-Induced Expression of CD11b on Human CD8+ Cells in vivo
Authors: Imrich Richard , Tibenska Elena , Koska Juraj , Rovensky Jozef , Vigas Milan
Published: April 2004

Objective: To study the short-term influences of pharmacologic hyperprolactinemia on hydrocortisone (HC)-induced effects on selected immune parameters. Methods: A single dose of HC (40 mg per os) was administered to eleven healthy female volunteers 1 h after domperidone (10 mg per os) or placebo administration. Immune cell subsets and expression of adhesion molecules was assessed by flow cytometry at baseline and 4 and 6 h after HC administration. Intracellular staining of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) production in CD4+ lymphocytes after phorbol myristate acetate and ionomycin stimulation was performed at the same time points. Results: HC administration was followed by a significant increase in cortisol levels, numbers of leukocytes and granulocytes and the percentage of CD16+, CD19+, CD11a+, CD11a+CD8+, CD11b+ and CD11b+CD8+ cells. The number of lymphocytes and monocytes and the percentage of CD3+, CD4+, CD4+/CD8+ ratio, CD62L+, CD54+ and CD54+CD16+ cells decreased, while the percentage of CD8+ cells was unaffected. Domperidone administration resulted in a significant increase in prolactin (PRL) concentrations. During hyperprolactinemia, the HC-induced increase in CD11b+CD8+ cells was significantly (p < 0.05) attenuated at 4 h. HC-induced changes in other immune parameters remained unaffected. No significant changes in the intracellular production of IL-4 and IFN-γ in CD4+ lymphocytes were observed after a single dose of HC alone or during hyperprolactinemia. Conclusions: This study shows an attenuated HC-induced increase in CD11b+CD8+ cells in the peripheral blood of healthy females during hyperprolactinemia. Our in vivo observations suggest that short-term interactions occur between PRL and glucocorticoids, affecting selected immune functions. Further studies are needed for confirmation of these results.
Adjuvante Therapie des Mammakarzinoms 2004
Authors: Kahlert S. , von Koch F. , Ditsch N. , Untch M.
Published: April 2004

Die aus kontrollierten randomisierten Studien gewonnenen Erkenntnisse haben zu einer weiten Verbreitung der adjuvanten endokrinen, zytostatischen oder chemoendokrinen Therapie geführt. Auch für die günstigsten Tumorstadien kann bei positivem Hormonrezeptorstatus eine endokrine Therapie empfohlen werden. Die 8. Konsensuskonferenz in St. Gallen über die Behandlung des Mammakarzinoms 2003 hat eine Vielfalt an Therapieoptionen für fast alle Patientinnen eröffnet. Schwerpunkte waren die Option einer adjuvanten Anastrozoltherapie für Frauen mit Tamoxifenkontraindikationen oder -unverträglichkeit und die Definition einer Gruppe «stärkerer» Chemotherapien für Hochrisikopatientinnen. Leider hat das Expertengremium keine klaren Empfehlungen abgegeben, weder für die Auswahl idealer Kandidatinnen für die reine endokrine Therapie (als Therapieoption für alle Patientinnen mit optimaler «endocrine responsiveness» oder Kontraindikationen gegen Chemotherapie) noch für die aggressiveren Therapieformen. In der Zwischenzeit haben neue oder aktualisierte Studien nützliche Zusatzinformationen für die gemeinsame Entscheidungsfindung mit den Patientinnen geliefert. Die kanadische MA.17-Studie zeigte einen signifikanten Vorteil durch eine Sequenztherapie mit Letrozol nach 5 Jahren Tamoxifen gegenüber nur 5 Jahren Tamoxifen. Zusammen mit aktualisierten Daten der ATAC-Studie und der italienischen ITA-Studie wird die Rolle der Aromataseinhibitoren als adjuvante Therapie kontinuierlich gestärkt. Einige Studien zeigten signifikante Vorteile bezüglich Rezidivfreiheit und/oder Überleben durch eine taxanhaltige Therapie im Vergleich mit einer taxanfreien Therapie. Diese Daten sollten Patientinnen unbedingt zugänglich gemacht werden. Im komplexen Prozess der Entscheidungsfindung sind ein umfassendes Wissen über die Studienlage und die frühe Einbeziehung der Patientin notwendig.
Neoadjuvant Hormone Treatment with Leuprolide Acetate Depot 3.75 mg and Cyproterone Acetate, before Radical Prostatectomy: A Randomized Study
Authors: Prezioso Domenico , Lotti Tullio , Polito Mario , Montironi Rodolfo
Published: April 2004

Objectives: To assess the effect of neoadjuvant hormone treatment before radical prostatectomy on: tumor/prostate volume, prostate-specific antigen (PSA) and testosterone levels, surgical margin status and tumor stage, and the ease of surgery following treatment. Methods: Patients with clinically localized prostatic carcinoma were randomized to receive leuprolide acetate depot 3.75 mg once a month for 3 months and cyproterone acetate 300 mg once a week for 3 weeks prior to surgery (group A). A control group of patients had surgery without any pretreatment (group B). Results: 167 patients were evaluated for the efficacy parameters. In group A, 31% of patients had a reduction in tumor/prostate volume following hormone therapy. PSA and testosterone levels were significantly reduced (p = 0.0001) in patients in group A compared to basal values. Centralized histopathological data evaluated in 145 patients (group A and 75 group B) showed that more patients in group B had tumors at stages T3A and T3B than in group A; this difference was close to significance (p = 0.057). Positive surgical margins were more common in group B (60% of patients) compared to group A (39% of patients). Similarly lymph node involvement was more common in group B compared to group A (11 versus 3%). There was little difference between the 2 study groups for the other surgical parameters assessed (ease of dissection, duration of surgery, blood loss). Conclusions: Neoadjuvant hormone therapy before radical prostatectomy has some effects in the treatment of prostate cancer. However, long-term follow-up of patients is needed to assess the impact of this therapy on morbidity and mortality.
The Clinical Usefulness of Prostate-Specific Antigen (PSA) Level and Age-Specific PSA Reference Ranges for Detecting Prostate Cancer in Chinese
Authors: Wu Tony T. , Huang Jong-Khing
Published: April 2004

Introduction: To determine the role of prostate-specific antigen (PSA) level and age-specific PSA reference ranges for detecting prostate cancer in Chinese. Material and Methods: We retrospectively reviewed the medical records of all 50- to 79-year-old men who had their first-time prostatic biopsy done at our institute between January 1998 and December 2000. We evaluated the effect on biopsy rate and cancer detection if the PSA cutoff was shifted from 4.0 ng/ml to the age-specific reference ranges. Also, we tried to develop age-adjusted PSA cutoffs for Chinese. Results: Among 1,236 men enrolled, 252 (20.4%) were diagnosed as prostate cancers. The positive predictive value was 22.2% for PSA >4.0 ng/ml. Using the traditional age-specific PSA reference ranges 134 (10.8%) biopsies could be avoided but five (1.98%) cancers would be missed. We proposed age-specific PSA reference ranges for Chinese as: 0–4.0 ng/ml for men in their 50s and 0–6.0 ng/ml for men between 60 and 79 years. Had we used these alternative cutoffs, 150 (12.1%) biopsies could be saved, of them 3 were cancers. Conclusions: The age-specific PSA reference ranges may help to avoid 12% of biopsies but 1.2% of prostate cancers would have gone undetected. Among population with low incidence of prostate cancer as Chinese, minimizing unnecessary biopsies might be more important issue than maximizing cancer detection rate.
Comparative Study between AudiovisualSexual Stimulation Test and Nocturnal Penile Tumescence Test Using RigiScan Plus in the Evaluatio n of Erectile Dysfunction
Authors: Mizuno Ichiro , Fuse Hideki , Fujiuchi Yasuyoshi , Nakagawa Osamu , Akashi Takuya
Published: April 2004

Introduction: Although the nocturnal penile tumescence (NPT) test is considered the gold standard for the differential diagnosis of psychogenic versus organic erectile dysfunction (ED), concerns have recently been raised regarding the financial and time expenditure it demands. We evaluated the diagnostic efficacy of the audiovisual sexual stimulation (AVSS) test as an alternative to the NPT test. Patients and Methods: A total of 43 patients with ED were examined. Each patient filled in an International Index of Erectile Function (IIEF) questionnaire. The evaluation of each patient consisted of AVSS and NPT tests which were performed using the RigiScan Plus. The results obtained with the two tests were compared. The patients with normal NPT patterns were presumed to have a psychogenic etiology of their ED and those with abnormal NPT patterns to have an organic etiology. Results: The overall IIEF score was 32.5 ± (SD) 9.2, and the erectile domain score was 12.2 ± 4.5. Twenty-three patients had normal responses to the AVSS test, while 20 had abnormal responses. Twenty-two of the former 23 patients and 9 of the latter 20 patients had normal NPT patterns. Therefore, the AVSS test discriminated psychogenic ED with 71% sensitivity and 92% specificity. The overall accuracy of the test in this study was 77%. Conclusions: The AVSS test is simple, practical, and inexpensive, and its diagnostic accuracy is comparable to that of the NPT test. We conclude that the AVSS test should be the examination of choice for the primary etiological diagnosis in ED.
Isolated Renal Tuberculosis following Intravesical Bacillus Calmette-Guérin Therapy for Bladder Cancer
Authors: Wada Yoshihiro , Sugiyama Yutaka , Kikukawa Hiroaki , Kuwahara Tomohiro , Takahashi Wataru , Takamiya Tomi , Ueda Shoichi
Published: April 2004

We present a case of isolated renal tuberculosis following bacillus Calmette-Guérin (BCG) therapy for bladder cancer. In the presurgical radiographic examination, we suspected an atypical renal cell carcinoma. According to the diagnosis of renal cell carcinoma, we performed a radical nephrectomy. The histological findings were tuberculosis-specific inflammatory changes and the patient received an antituberculous multiple drug therapy for a year. It is concluded that we should pay attention to the possibility of a renal tuberculosis granuloma in any patient who presented with subacute formed renal masses following BCG treatment before deciding on the strategy of the treatment of the renal masses, especially in patients who had received such a treatment which induced an immunocompromised state.
A Multidrug Efflux Pump Inhibitor Reduces Fluoroquinolone Resistance in Pseudomonas aeruginosa Isolates
Authors: Coban Ahmet Yilmaz , Ekinci Bora , Durupinar Belma
Published: April 2004

In general, resistance to fluoroquinolones (FQs) in gram-negative bacteria is acquired either by mutations in DNA gyrase and topoisomerase IV or by active export of the agents via antibiotic efflux pumps. Reduced porin expression is also proposed to be another mechanism leading to resistance. In this study, interaction between levofloxacin, ofloxacin, and ciprofloxacin with MC-207,110 (multidrug efflux pump inhibitor) was investigated by a checkerboard assay using Pseudomonas aeruginosa. Levofloxacin, ofloxacin, and ciprofloxacin were tested at different concentrations (0.06–64 µg/ml) and MC-207,110 was tested at a concentration range of 4–128 µg/ml. In the presence of MC-207,110 (at 128, 64, 32, 16 µg/ml) resistance to FQs was inhibited significantly and MIC values were decreased, except at 8 and 4 µg/ml of MC-207,110. When MC-207,110 was used, resistance of P. aeruginosa to FQs in vitro was inhibited significantly, suggesting that MC-207,110 may be useful for use in clinical treatment protocols to overcome FQs resistance.
Comparative Activity of β-Lactam Agents (Carbapenem Excepted) against Pseudomonas aeruginosa Strains with CARB or OXA β-Lactamases
Authors: Bert Frédéric , Branger Catherine , Lambert-Zechovsky Nicole
Published: April 2004

Background: Ticarcillin resistance in Pseudomonas aeruginosa can be mediated by various β-lactamases of the CARB and OXA groups. Methods: We investigated the activity of seven β-lactam agents and two β-lactam-β-lactamase inhibitor combinations against 216 P.aeruginosa strains with genotypically characterized β-lactamases, including 137 CARB, 31 OXA-35, 25 OXA-10, 13 OXA-1 and 10 OXA-2. MICs were determined by the agar dilution method. Results: The activities of ticarcillin and piperacillin were more affected by CARB than by OXA enzymes. β-Lactamase inhibitors were poorly effective against OXA-1, OXA-35 and OXA-10. OXA-1 conferred resistance to cefepime and cefpirome but not to cefsulodin and aztreonam. Ceftazidime remained the most active agent against all groups of enzymes. Major differences in the susceptibility rates according to NCCLS and CASFM breakpoints were observed. Conclusion: Significant differences were found in the resistance profile associated with the various types of CARB and OXA β-lactamases in P. aeruginosa.
Influenza and Pneumococcal Vaccinations Fail to Prevent Myocardial Infarction
Authors: Meyers David G. , Beahm D. David , Jurisich Peter D. , Milford Christopher J. , Edlavich Stanley
Published: April 2004

Background: Four observational studies and one clinical trial have suggested that influenza vaccination is associated with a >50% reduction in risk of cardiac sudden death, myocardial infarction (MI), and stroke. One observational study found no effect. Objective: To identify an association between influenza or pneumococcal vaccination and myocardial infarction. Methods: We conducted a case-control study of discharges from nine metropolitan hospitals to identify a possible association between both influenza and pneumococcal vaccinations and MI, using patients with bone fractures as controls. We administered a standardized questionnaire to 335 MI patients and 199 patients with fractures (76% of eligible patients). Results: The groups significantly differed by sex, age, body mass index, smoking status, family history of heart disease, personal history of cardiovascular disease, and number of self-reported upper respiratory infections both during the winter months of interest and in the two weeks prior to their index event. Influenza vaccine had been administered to 177 (53%) MI patients and 126 (63%) fracture patients (p = 0.049) with an adjusted odds ratio (OR) = 0.90 (95% confidence interval 0.60, 1.35), p = 0.593. In 148 pairs matched by age and sex, the post hoc adjusted OR = 0.97. Pneumococcal vaccine had been administered to 107 (32%) MI patients and 78 (39%) fracture patients (p = 0.203) with an adjusted OR = 0.89 (95% confidence interval 0.60, 1.33), p = 0.577, and a power = 0.96 to detect a difference ≧40%. Conclusions: Neither influenza nor pneumococcal vaccine is associated with a reduced risk of myocardial infarction. A randomized controlled trial is needed.
An Attempt to Determine the Benefits of a ‘Home-for-Life’ Principle in Residential Care for People with Dementia and Behavioural Problems: A Comparative Cohort Study
Authors: Macdonald Alastair , Philpot Michael , Briggs Catherine
Published: April 2004

It is not clear whether moving individuals with dementia and behavioural problems as part of a rehabilitation and relocation (‘intermediate care’, IC) nursing home model worsens behaviour, compared with a ‘home for life’ philosophy. We studied this in contiguous services with the same formal admission criteria but different models of subsequent care. 37 patients admitted to ‘homes for life’ and 24 to IC homes were followed up for 1 year using the BEHAVE-AD. Scores were lower at baseline in the IC group. Both groups deteriorated over the year, although more in IC patients (trend), and those actually moving home were worse after the move. Use of neuroleptic medication increased significantly in the IC group. Our results confirm previous studies of the disruptive effects of re-location for patients with severe dementia but do not suggest major differences between the two models of care.
Donepezil for Alzheimer’s Disease in Clinical Practice – The DONALD Study
Authors: Froelich L. , Gertz H.-J. , Heun R. , Heuser I. , Jendroska K. , Kornhuber J. , Kurz A. , Mueller-Thomsen T. , Ries F. , Waechtler C. , Metz M. , Goebel C.
Published: April 2004

This multicenter open-label clinical trial was designed to investigate the safety and efficacy of donepezil, a selective acetylcholinesterase inhibitor, in the treatment of Alzheimer’s disease (AD) in routine clinical practice in Germany. A total of 237 patients with mild-to-moderate AD were treated with donepezil for 24 weeks, 186 completed the study according to the protocol. In the completer group, mean MMSE score for efficacy showed an improvement from baseline of +1.6 points at week 12 (95% CI +1.1 to +2.1) and of +1.1 points at week 24 (95% CI +0.5 to +1.7). In more than 80% of the patients, global tolerability was rated to be very good or good. There were only insignificant effects on ECG parameters. This study confirms the results obtained in previous double-blind trials, which showed that donepezil is effective and well tolerated in patients with mild-to-moderately severe AD.
An Anti-VEGF Ribozyme Embedded within the Adenoviral VAI Sequence Inhibits Glioblastoma Cell Angiogenic Potential in vitro
Authors: Ciafrè Silvia Anna , Niola Francesco , Wannenes Francesca , Farace Maria Giulia
Published: April 2004

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis, where it functions as one of the major angiogenic factors sustaining growth and draining catabolites. In this study, we developed an anti-VEGF ribozyme targeted to the 5′ part of human VEGF mRNA. We endowed this ribozyme with an additional feature expected to improve its activity in vivo, by cloning it into a VAI transcriptional cassette. VAI is originally part of the adenovirus genome, and is characterized by high transcription rates, good stability due to its strong secondary structure and cytoplasmic localization. Transfection of U87 human glioblastoma cells with plasmid vectors encoding for this ribozyme resulted in a strong (–56%) reduction of VEGF secreted in the extracellular medium, indicating a good biological activity of the ribozyme. Moreover, this reduction in VEGF secretion had the important functional consequence of drastically diminishing the formation of tube-like structures of human umbilical vascular endothelial cells in a Matrigel in vitro angiogenesis assay. In conclusion, our VAI-embedded anti-VEGF ribozyme is a good inhibitor of angiogenesis in vitro, in a glioblastoma cell context. Thus, it may represent a useful tool for future applications in vivo, for antiangiogenic gene therapy of glioblastoma and of highly vascularized tumors.
Factor XI–Dependent Reciprocal Thrombin Generation Consolidates Blood Coagulation when Tissue Factor Is Not Available
Authors: Wielders Simone J.H. , Béguin Suzette , Hemker H. Coenraad , Lindhout Theo
Published: April 2004

Objective—

Feedback activation of factor XI by thrombin is a likely alternative for tissue factor-dependent propagation of thrombus formation. However, the hypothesis that thrombin can initiate and propagate its formation in a factor XI-dependent and platelet-dependent manner has not been tested in a plasma milieu.

Methods and Results—

We investigated thrombin generation in recalcified platelet-rich plasma activated with varying amounts of thrombin or factor VIIa. Thrombin initiates and propagates dose-dependently thrombin generation only when platelets and plasma factor XI are present. Incubation of thrombin-activated platelets with a tissue factor neutralizing antibody had no effect on thrombin formation, indicating that platelet-associated tissue factor, if present at all, is not involved. In the absence of factor VIII, thrombin could not initiate its own formation, whereas factor VIIa-induced thrombin generation was reduced. Collagen strongly stimulated both thrombin-initiated and factor VIIa-initiated thrombin generation.

Conclusions—

These findings support the notion that platelet-localized feedback activation of factor XI by thrombin plays an important role in maintaining normal hemostasis as well as in sustaining thrombus formation when the TF pathway is inhibited by tissue factor pathway inhibitor.
Circulating Tissue Kallikrein Levels Correlate With Severity of Carotid Atherosclerosis
Authors: Porcu Paolo , Emanueli Costanza , Desortes Elisa , Marongiu Giovanni M. , Piredda Franco , Chao Lee , Chao Julie , Madeddu Paolo
Published: April 2004

Background—

Vascular growth factors are upregulated in stroke patients, but it remains unknown if they correlate with carotid atherosclerosis.

Methods and Results—

A case-control study was conducted to determine: (1) possible association between biomarkers of angiogenesis or inflammation and carotid stenosis; and (2) the impact of revascularization on the same biomarkers. Circulating vascular endothelial growth factor (VEGF), basic fibroblast GF (bFGF), tissue kallikrein (tK), and high-sensitivity C-reactive protein (hs-CRP) were measured in 89 patients with carotid obstruction and 45 age-matched controls. Patients were stratified as <50% carotid stenosis (CAS; n=16); 50% to 69% CAS (n=12); 70% to 99% CAS (n=43); and carotid occlusion (CAO; n=18). No association was found between VEGF, bFGF, or hs-CRP and obstruction grading. TK augmented from 360±30 in <50% CAS (
P
=NS versus controls) to 509±72 in moderate CAS (
P
<0.05), 1159±178 in high-grade CAS (
P
<0.02), and 1616±403 pg/mL in CAO (
P
<0.01). A threshold of 508 pg/mL provided the maximized predictive value of high-grade obstruction. After revascularization, tK decreased from 1410±352 to 782±86 pg/mL (
P
<0.01), whereas no change was detected in nonoperated cases. Hs-CRP was unaffected by revascularization.

Conclusions—

Angiogenic factors are heterogeneously expressed in patients with carotid atherosclerosis. The tK measurement may be useful for the diagnosis and monitoring of atherosclerotic disease.