bluuebunny/crossref_metadata_2025 huggingface dataset:
Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia
Authors: Grenz Almut , Zhang Hua , Weingart Jochen , von Wietersheim Simone , Eckle Tobias , Schnermann Juergen , Köhle Christoph , Kloor Doris , Gleiter Christoph H. , Vallon Volker , Eltzschig Holger K. , Osswald Hartmut
Published: September 2007

Previous studies have yielded conflicting results as to whether extracellular adenosine generation and signaling contributes to hypoxia-induced increases in renal erythropoietin (EPO) secretion. In this study, we combined pharmacological and genetic approaches to elucidate a potential contribution of extracellular adenosine to renal EPO release in mice. To stimulate EPO secretion, we used murine carbon monoxide exposure (400 and 750 parts per million CO, 4 h), ambient hypoxia (8% oxygen, 4 h), or arterial hemodilution. Because the ecto-5-nucleotidase (CD73, conversion of AMP to adenosine) is considered the pacemaker of extracellular adenosine generation, we first tested the effect of blocking extracellular adenosine generation with the specific CD73-inhibitor adenosine 5′-(α,β-methylene) diphosphate (APCP) or by gene-targeted deletion of cd73. These studies showed that neither APCP-treatment nor targeted deletion of cd73 resulted in changes of stimulated EPO mRNA or serum levels, although the increases of adenosine levels in the kidney following CO exposure were attenuated in mice with APCP treatment or in cd73−/−mice. Moreover, pharmacological studies using specific inhibitors of individual adenosine receptors (A1AR, DPCPX; A2AAR, DMPX; A2BAR, PSB 1115; A3AR, MRS 1191) showed no effect on stimulated increases of EPO mRNA or serum levels. Finally, stimulated EPO secretion was not attenuated in gene-targeted mice lacking A1AR−/−, A2AAR−/−, A2BAR−/−, or A3AR−/−. Together, these studies combine genetic and pharmacological in vivo evidence that increases of EPO secretion during limited oxygen availability are not affected by extracellular adenosine generation or signaling.
Critical roles of Sp1 in gene expression of human and rat H+/organic cation antiporter MATE1
Authors: Kajiwara Moto , Terada Tomohiro , Asaka Jun-ichi , Ogasawara Ken , Katsura Toshiya , Ogawa Osamu , Fukatsu Atsushi , Doi Toshio , Inui Ken-ichi
Published: September 2007

A H+/organic cation antiporter (multidrug and toxin extrusion 1: MATE1/SLC47A1) plays important roles in the tubular secretion of various clinically important cationic drugs such as cimetidine. We have recently found that the regulation of this transporter greatly affects the pharmacokinetic properties of cationic drugs in vivo. No information is available about the regulatory mechanisms for the MATE1 gene. In the present study, therefore, we examined the gene regulation of human (h) and rat (r) MATE1, focusing on basal expression. A deletion analysis suggested that the regions spanning −65/−25 and −146/−38 were essential for the basal transcriptional activity of the hMATE1 and rMATE1 promoter, respectively, and that both regions contained putative Sp1-binding sites. Functional involvement of Sp1 was confirmed by Sp1 overexpression, a mutational analysis of Sp1-binding sites, mithramycin A treatment, and an electrophoretic mobility shift assay. Furthermore, we found a single nucleotide polymorphism (SNP) in the promoter region of hMATE1 (G−32A), which belongs to a Sp1-binding site. The allelic frequency of this rSNP was 3.7%, and Sp1-binding and promoter activity were significantly decreased. This is the first study to clarify the transcriptional mechanisms of the MATE1 gene and to identify a SNP affecting the promoter activity of hMATE1.
Hypoxia has a greater effect than exercise on the redistribution of pulmonary blood flow in swine
Authors: Hopkins Susan R. , Kleinsasser Axel , Bernard Susan , Loeckinger Alex , Falor Eric , Neradilek Blazej , Polissar Nayak L. , Hlastala Michael P.
Published: September 2007

Strenuous exercise combined with hypoxia is implicated in the development of high-altitude pulmonary edema (HAPE), which is believed to result from rupture of pulmonary capillaries secondary to high vascular pressures. The relative importance of hypoxia and exercise in altering the distribution of pulmonary blood flow (PBF) is unknown. Six chronically catheterized specific pathogen-free Yorkshire hybrid pigs (25.5 ± 0.7 kg, means ± SD) underwent incremental treadmill exercise tests in normoxia (FiO2 = 0.21) and hypoxia (FiO2 = 0.125, balanced order), consisting of 5 min at 30, 60, and 90% of the previously determined V̇o2max. At steady state (∼4 min), metabolic and cardiac output data were collected and fluorescent microspheres were injected over ∼30 s. Later the fluorescent intensity of each color in each 2-cm3 lung piece was determined and regional perfusion was calculated from the weight-normalized fluorescence. Both hypoxia and exercise shifted PBF away from the ventral cranial lung regions toward the dorsal caudal regions of the lung, but hypoxia caused a greater dorsal caudal shift in PBF at rest than did near-maximal exercise in normoxia. The variance in PBF due to hypoxia, exercise, and vascular structure was 16 ± 4.2, 4.0 ± 4.4, and 59.4 ± 11.4%, respectively, and the interaction between hypoxia and exercise represented 12 ± 6.5%. This observation implies that there is already a maximal shift with in PBF with hypoxia in the dorsal-caudal regions in pigs that cannot be exceeded with the addition of exercise. However, exercise greatly increases the pulmonary arterial pressures and therefore the risk of capillary rupture in high flow regions.
Combined aerobic and resistance training and vascular function: effect of aerobic exercise before and after resistance training
Authors: Okamoto Takanobu , Masuhara Mitsuhiko , Ikuta Komei
Published: September 2007

Aerobic exercise training combined with resistance training (RT) might prevent the deterioration of vascular function. However, how aerobic exercise performed before or after a bout of RT affects vascular function is unknown. The present study investigates the effect of aerobic exercise before and after RT on vascular function. Thirty-three young, healthy subjects were randomly assigned to groups that ran before RT (BRT: 4 male, 7 female), ran after RT (ART: 4 male, 7 female), or remained sedentary (SED: 3 male, 8 female). The BRT and ART groups performed RT at 80% of one repetition maximum and ran at 60% of the targeted heart rate twice each week for 8 wk. Both brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) after combined training in the BRT group did not change from baseline. In contrast, baPWV after combined training in the ART group reduced from baseline (from 1,025 ± 43 to 910 ± 33 cm/s, P < 0.01). Moreover, brachial artery FMD after combined training in the ART group increased from baseline (from 7.3 ± 0.8 to 9.6 ± 0.8%, P < 0.01). Brachial artery diameter, mean blood velocity, and blood flow in the BRT and ART groups after combined training increased from baseline ( P < 0.05, P < 0.01, and P < 0.001, respectively). These values returned to the baseline during the detraining period. These values did not change in the SED group. These results suggest that although vascular function is not improved by aerobic exercise before RT, performing aerobic exercise thereafter can prevent the deteriorating of vascular function.
Combined isometric, concentric, and eccentric resistance exercise prevents unloading-induced muscle atrophy in rats
Authors: Adams G. R. , Haddad F. , Bodell P. W. , Tran P. D. , Baldwin K. M.
Published: September 2007

Previously, we reported that an isometric resistance training program that was effective in stimulating muscle hypertrophy in ambulatory rats could not completely prevent muscle atrophy during unloading (Haddad F, Adams GR, Bodell PW, Baldwin KM. J Appl Physiol 100: 433–441, 2006). These results indicated that preventing muscle atrophy does not appear to be simply a function of providing an anabolic stimulus. The present study was undertaken to determine if resistance training, with increased volume (3-s contractions) and incorporating both static and dynamic components, would be effective in preventing unloading-induced muscle atrophy. Rats were exposed to 5 days of muscle unloading via tail suspension. During that time one leg received electrically stimulated resistance exercise (RE) that included an isometric, concentric, and eccentric phase. The results of this study indicate that this combined-mode RE provided an anabolic stimulus sufficient to maintain the mass and myofibril content of the trained but not the contralateral medial gastrocnemius (MG) muscle. Relative to the contralateral MG, the RE stimulus increased the amount of total RNA (indicative of translational capacity) as well as the mRNA for several anabolic/myogenic markers such as insulin-like growth factor-I, myogenin, myoferlin, and procollagen III-α-1 and decreased that of myostatin, a negative regulator of muscle size. The combined-mode RE protocol also increased the activity of anabolic signaling intermediates such as p70S6 kinase. These results indicate that a combination of static- and dynamic-mode RE of sufficient volume provides an effective stimulus to stimulate anabolic/myogenic mechanisms to counter the initial stages of unloading-induced muscle atrophy.
End-expiratory and tidal volumes measured in conscious mice using single projection x-ray images
Authors: Lai-Fook Stephen J. , Houtz Pamela K. , Lai Yih-Loong
Published: September 2007

The evaluation of airway resistance (Raw) in conscious mice requires both end-expiratory (Ve) and tidal volumes (Vt) (Lai-Fook SJ and Lai YL. J Appl Physiol 98: 2204–2218, 2005). In anesthetized BALB/c mice we measured lung area (AL) from ventral-to-dorsal x-ray images taken at FRC (Ve) and after air inflation with 0.25 and 0.50 ml (ΔVL). Total lung volume (VL) described by equation: VL= ΔVL+ VFRC= KAL1.5assumed uniform (isotropic) inflation. Total VFRCaveraged 0.55 ml, consisting of 0.10 ml tissue, 0.21 ml blood and 0.24 ml air. K averaged 1.84. In conscious mice in a sealed box, we measured the peak-to-peak box pressure excursions (ΔPb) and x-rays during several cycles. K was used to convert measured AL1.5to VLvalues. We calculated Veand Vtfrom the plot of VLvs. cos(α − φ). Phase angle α was the minimum point of the Pbcycle to the x-ray exposure. Phase difference between the Pband VLcycles (φ) was measured from ΔPbvalues using both room- and body-temperature humidified box air. A similar analysis was used after aerosol exposures to bronchoconstrictor methacholine (Mch), except that φ depended also on increased Raw. In conscious mice, Ve(0.24 ml) doubled after Mch (50–125 mg/ml) aerosol exposure with constant Vt, frequency (f), ΔPb, and Raw. In anesthetized mice, in addition to an increased Ve, repeated 100 mg/ml Mch exposures increased both ΔPband Rawand decreased f to apnea in 10 min. Thus conscious mice adapted to Mch by limiting Raw, while anesthesia resulted in airway closure followed by diaphragm fatigue and failure.
Allergic lung inflammation affects central noradrenergic control of cholinergic outflow to the airways in ferrets
Authors: Wilson Christopher G. , Akhter Shamima , Mayer Catherine A. , Kc Prabha , Balan Kannan V. , Ernsberger Paul , Haxhiu Musa A.
Published: September 2007

Brain stem noradrenergic cell groups mediating autonomic responses to stress project to airway-related vagal preganglionic neurons (AVPNs). In ferrets, their activation produces withdrawal of cholinergic outflow to the airways via release of norepinephrine and activation of α2A-adrenergic receptors (α2A-AR) expressed by AVPNs. In these studies, we examined the effects of allergen exposure of the airway (AE) with ovalbumin on noradrenergic transmission regulating the activity of AVPNs and, consequently, airway smooth muscle tone. Experiments were performed in vehicle control (Con) and AE ferrets. Microperfusion of an α2A-AR agonist (guanabenz) in close proximity to AVPNs elicited more pronounced effects in Con than AE ferrets, including a decrease in unit activity and reflexly evoked responses of putative AVPN neurons with a corresponding decrease in cholinergic outflow to the airways. Although no differences were found in the extent of noradrenergic innervation of the AVPNs, RT-PCR and Western blot studies demonstrated that AE and repeated exposure to antigen significantly reduced expression of α2A-ARs at message and protein levels. These findings indicate that, in an animal model of allergic asthma, sensitization and repeated challenges with a specific allergen diminish central inhibitory noradrenergic modulation of AVPNs, possibly via downregulation of α2A-AR expression by these neurons.
The effect of increased background resistance on the resistive load threshold for eliciting the respiratory-related evoked potential
Authors: Chou Yang Ling , Davenport Paul W.
Published: September 2007

The detection threshold (ΔR50) of resistive (R) loads is a function of the total background resistance (R0). Increased R0 increases the ΔR50, but the ratio ΔR50/R0 remains constant. The respiratory-related evoked potential (RREP) is elicited only by R loads greater than the cognitive detection threshold, ΔR50. We hypothesized that the RREP Nf, P1, and N1 peaks will be elicited only when the added load ΔR/R0 is greater than the normal detection threshold, ΔR50/R0 = 0.30. We also hypothesized that when the R0 is increased by adding extrinsic R, the RREP will not be elicited if the ΔR/R0 is less than the 0.30 ratio. RREPs were recorded with healthy volunteers ( n = 20) respiring through a non-rebreathing valve. Three inspiratory R loads that spanned the ΔR50/R0 = 0.30 detection threshold were presented in two conditions: 1) no added R0 (R1 < 0.30, R2 > 0.30, R3 > 0.30); and 2) increased R0 = 13.3 cmH2O·l−1·s (R1 < 0.30, R2 < 0.30, R3 > 0.30). For the control R0, P1, Nf, and N1 peaks of the RREP were elicited by both R2 and R3, and not present with R1. The increased R0 decreased R2/R0 > 1.5 to R2/R0 < 0.15. With increased R0, the R1 and R2 loads did not elicit the RREP, but the Nf, P1, and N1 peaks were present for R3. These results demonstrate that the RREP is present if the ΔR is above the cognitive detection threshold, and the RREP is absent if the load is below the detection threshold. When the R0 is increased to make the ΔR/R0 less than the detection threshold, the ΔR no longer elicits the RREP.
Alterations in GABAA Receptor Mediated Inhibition in Adjacent Dorsal Midline Thalamic Nuclei in a Rat Model of Chronic Limbic Epilepsy
Authors: Rajasekaran Karthik , Kapur Jaideep , Bertram Edward H.
Published: September 2007

There is evidence that the dorsal midline thalamus is involved in the seizures of limbic epilepsy. However, little is known about the inhibitory synaptic function in this region. In the present study, inhibitory postsynaptic currents (IPSCs) mediated by GABAA receptors were recorded from the mediodorsal (MD) and paraventricular (PV) nuclei from control and epileptic animals. In the MD, the spontaneous (s)IPSCs for epileptic animals had a lower frequency, prolonged rise time, prolonged decay, but unaltered net charge transfer compared with controls. The miniature (m)IPSC parameters were unaltered in the epileptic animals. In contrast, in the PV, both sIPSCs and mIPSCs in the epileptic animals were more frequent with larger amplitudes and there was an increase in the net charge transfer compared with controls. The rise times of the sIPSCs of the PV neurons were significantly prolonged, whereas the weighted decay time of the mIPSC was significantly shortened in epileptic animals. These findings suggest that the changes associated with inhibitory synaptic transmission in limbic epilepsy are not uniform across regions in the thalamus that are part of the seizure circuit.
Difficulty of Visual Search Modulates Neuronal Interactions and Response Variability in the Frontal Eye Field
Authors: Cohen Jeremiah Y. , Pouget Pierre , Woodman Geoffrey F. , Subraveti Chenchal R. , Schall Jeffrey D. , Rossi Andrew F.
Published: September 2007

The frontal eye field (FEF) is involved in selecting visual targets for eye movements. To understand how populations of FEF neurons interact during target selection, we recorded activity from multiple neurons simultaneously while macaques performed two versions of a visual search task. We used a multivariate analysis in a point process statistical framework to estimate the instantaneous firing rate and compare interactions among neurons between tasks. We found that FEF neurons were engaged in more interactions during easier visual search tasks compared with harder search tasks. In particular, eye movement–related neurons were involved in more interactions than visual-related neurons. In addition, our analysis revealed a decrease in the variability of spiking activity in the FEF beginning ∼100 ms before saccade onset. The minimum in response variability occurred ∼20 ms earlier for the easier search task compared with the harder one. This difference is positively correlated with the difference in saccade reaction times for the two tasks. These findings show that a multivariate analysis can provide a measure of neuronal interactions and characterize the spiking activity of FEF neurons in the context of a population of neurons.
Olfactory Coding With All-or-Nothing Glomeruli
Authors: Koulakov Alexei , Gelperin Alan , Rinberg Dmitry
Published: September 2007

We present a model for olfactory coding based on spatial representation of glomerular responses. In this model distinct odorants activate specific subsets of glomeruli, dependent on the odorant's chemical identity and concentration. The glomerular response specificities are understood statistically, based on experimentally measured distributions of activation thresholds. A simple version of the model, in which glomerular responses are binary (the all-or-nothing model), allows us to account quantitatively for the following results of human/rodent olfactory psychophysics: 1) just noticeable differences in the perceived concentration of a single odor (Weber ratios) are as low as d C/ C ≃ 0.04; 2) the number of simultaneously perceived odors can be as high as 12; and 3) extensive lesions of the olfactory bulb do not lead to significant changes in detection or discrimination thresholds. We conclude that a combinatorial code based on a binary glomerular response is sufficient to account for several important features of the discrimination capacity of the mammalian olfactory system.
Noise-Induced Transition to Bursting in Responses of Paddlefish Electroreceptor Afferents
Authors: Neiman Alexander B. , Yakusheva Tatyana A. , Russell David F.
Published: September 2007

The response properties of ampullary electroreceptors of paddlefish, Polyodon spathula, were studied in vivo, as single-unit afferent responses to external electrical stimulation with varied intensities of several types of noise waveforms, all Gaussian and zero-mean. They included broadband white noise, Ornstein–Uhlenbeck noise, low- or high-frequency band-limited noise, or natural noise recorded from swarms of Daphnia zooplankton prey, or from individual prey. Normally the afferents fire spontaneously in a tonic manner, which is actually quasiperiodic due to embedded oscillators. 1) Weak noise stimuli increased the variability of afferent firing, but it remained tonic. 2) In contrast, stimulation with less-weak broadband noise led to a qualitative change of the firing patterns, to parabolic bursting, even though the mean firing rate was scarcely affected. 3) The transition to afferent bursting was marked by the development of two well-separated timescales: the fast frequency of spiking inside bursts at ≤250 spikes/s and the slow frequency of burst occurrences at about 9 (range 5–13) bursts/s. These two timescales were manifested as two regimes in afferent power spectra, bimodal interspike interval histograms, return maps, and autocorrelation functions of afferent spike trains. 4) The stochastic approximately 9-Hz bursts were not simply driven by similar-frequency components of noise stimuli because bursts could be dissociated from stimulus waveforms using high-pass filtered noise, or a 0.1-Hz sine-wave stimulus. 5) Arrhenius plots showed that the threshold noise intensity required to elicit bursting depended on the frequency content of a noise stimulus, being lowest, about 1.2 μV/cm, for stimuli matching the 1- to 20-Hz best response band of these cathodally excited ampullary electroreceptors. This is only slightly higher than previous behavioral estimates of the electrosensory threshold as 0.5 μV/cm. 6) Comparable threshold values for bursting came from an alternate analytical approach, based on correlation times of spike trains. 7) Simultaneous recordings from pairs of afferents showed that their bursting frequencies (bursts/s) always converged as the amplitude of a noise stimulus was raised. Thus the slow timescale of bursting is similar for different electroreceptors, even though their mean spiking rates can differ. In conclusion, the ampullary electroreceptors of paddlefish have two distinct modes of operation: their spontaneous tonic firing is modulated by the weakest stimuli, but they switch to bursting output for less-weak stimuli. We propose that afferent bursting may mediate close-range tracking of planktonic prey.
Serpin Peptidase Inhibitor Clade A Member 1 as a Potential Marker for Malignancy in Insulinomas
Authors: de Sá Sandra Valéria , Corrêa-Giannella Maria Lúcia , Machado Márcio Carlos , Krogh Karin , de Almeida Madson Queiroz , Albergaria Pereira Maria Adelaide , Coelho Siqueira Sheila Aparecida , Patzina Rosely Antunes , Ibuki Felícia Satie , Sogayar Mari Cleide , Machado Marcel Cerqueira César , Giannella-Neto Daniel
Published: September 2007

Purpose: The biological behavior of insulinomas cannot be predicted based on histopathologic criteria in which the diagnosis of malignancy is confirmed by the presence of metastases. In this study, microarray and quantitative real-time reverse transcription-PCR were applied to identify differentially expressed genes between malignant and nonmalignant insulinomas to search for useful biomarkers to recognize the metastatic potential of insulinomas.

Experimental Design: CodeLink human bioarrays were used to analyze differences in ∼20,000 genes between six well-differentiated endocrine tumors of benign behavior compared with one well-differentiated endocrine carcinoma (WDEC) and three metastases of endocrine carcinomas (MEC). Quantitative real-time reverse transcription-PCR was used to validate differential expressions of five genes in a series of 35 sporadic insulinomas. Serpin peptidase inhibitor clade A member 1 (SERPINA1; α-1-antitrypsin) expression, identified as up-regulated in malignant insulinomas, was also evaluated by immunohistochemistry.

Results: Analysis of microarray data resulted in 230 differentially expressed genes. Gene Ontology analysis identified serine-type endopeptidase activity and serine-type endopeptidase inhibitor activity as pathways presenting significant differential expression. Protease serine 2 and complement factor B (from serine-type endopeptidase activity pathway) were respectively confirmed as up-regulated in well-differentiated endocrine tumors of benign behavior (WDET) and in WDEC/MEC. Angiotensinogen and SERPINA1 (from serine-type endopeptidase inhibitor activity pathway) were confirmed as up-regulated in WDEC/MEC. SERPINA1 was shown to be expressed in 85.7% of malignant versus 14.3% of nonmalignant insulinomas by immunohistochemistry.

Conclusions: Our data are consistent to the possibility that SERPINA1 is a marker of malignancy in insulinomas. Given the widespread availability of antibody anti-α-1-antitrypsin in pathology services, SERPINA1 expression evaluation might be of clinical utility in recognizing patients more likely to develop an aggressive presentation.
Genetically Targeted T Cells Eradicate Systemic Acute Lymphoblastic Leukemia Xenografts
Authors: Brentjens Renier J. , Santos Elmer , Nikhamin Yan , Yeh Raymond , Matsushita Maiko , La Perle Krista , Quintás-Cardama Alfonso , Larson Steven M. , Sadelain Michel
Published: September 2007

Purpose: Human T cells targeted to the B cell–specific CD19 antigen through retroviral-mediated transfer of a chimeric antigen receptor (CAR), termed 19z1, have shown significant but partial in vivo antitumor efficacy in a severe combined immunodeficient (SCID)-Beige systemic human acute lymphoblastic leukemia (NALM-6) tumor model. Here, we investigate the etiologies of treatment failure in this model and design approaches to enhance the efficacy of this adoptive strategy.

Experimental Design: A panel of modified CD19-targeted CARs designed to deliver combined activating and costimulatory signals to the T cell was generated and tested in vitro to identify an optimal second-generation CAR. Antitumor efficacy of T cells expressing this optimal costimulatory CAR, 19-28z, was analyzed in mice bearing systemic costimulatory ligand-deficient NALM-6 tumors.

Results: Expression of the 19-28z CAR, containing the signaling domain of the CD28 receptor, enhanced systemic T-cell antitumor activity when compared with 19z1 in treated mice. A treatment schedule of 4 weekly T-cell injections, designed to prolong in vivo T-cell function, further improved long-term survival. Bioluminescent imaging of tumor in treated mice failed to identify a conserved site of tumor relapse, consistent with successful homing by tumor-specific T cells to systemic sites of tumor involvement.

Conclusions: Both in vivo costimulation and repeated administration enhance eradication of systemic tumor by genetically targeted T cells. The finding that modifications in CAR design as well as T-cell dosing allowed for the complete eradication of systemic disease affects the design of clinical trials using this treatment strategy.
Platelets Take Up the Monoclonal Antibody Bevacizumab
Authors: Verheul Henk M.W. , Lolkema Martijn P.J. , Qian David Z. , Hilkes Yvonne H.A. , Liapi Eleni , Akkerman Jan-Willem N. , Pili Roberto , Voest Emile E.
Published: September 2007

Purpose: One of the key factors that promotes angiogenesis is vascular endothelial growth factor (VEGF). Platelets are the main source of VEGF in blood and contribute to angiogenesis by release of growth factors, including VEGF, from their α-granules on activation. The monoclonal antibody bevacizumab blocks VEGF in the blood of patients within hours after administration. Platelets are known to endocytose plasma proteins including immunoglobulins. We tested the hypothesis that platelets take up bevacizumab.

Experimental Design: Fluorescence-activated cell sorting analysis, immunofluorescence imaging, and Western blotting were used to study uptake and release of bevacizumab by platelets in vitro and in vivo. The angiogenic activity of platelets preincubated with bevacizumab was studied in endothelial proliferation assays. Finally, we determined whether treatment with bevacizumab neutralizes VEGF in platelets from cancer patients.

Results: We found that platelets are able to take up bevacizumab. Activation of platelets preincubated with bevacizumab resulted in release of the antibody and release of VEGF neutralized by bevacizumab. Immunofluorescence microscopy revealed that FITC-labeled bevacizumab and P-selectin colocalize, indicating α-granule localization. In addition, bevacizumab uptake inhibited platelet-induced human endothelial cell proliferation. In in vivo rabbit experiments, FITC-labeled bevacizumab was present in platelets after 2 h and up to 2 weeks following i.v. administration. Finally, we found that platelets take up bevacizumab in patients receiving bevacizumab treatment. Within 8 h after bevacizumab administration, platelet VEGF was almost completely neutralized due to this uptake.

Conclusion: These studies show that bevacizumab is taken up by platelets and may explain its clinical effect on wound healing and tumor growth.
Changing Pattern of Drug Abuse among Patients Entering Treatment in Lazio, Italy, between 1996 and 2003: Transition from Heroin to Cocaine Use
Authors: Davoli Marina , Pasqualini Fulvia , Belleudi Valeria , Bargagli Anna Maria , Perucci Carlo A.
Published: September 2007

Aim: This study describes temporal changes of the pattern of substance abuse among drug users in treatment in Lazio, Italy. Methods: We used individual data from the surveillance system of drug users of the Lazio region. We measured temporal changes in: the number of drug users in treatment, main and any substance of abuse, and mode of referral to treatment. Results: Among new clients, the proportion of heroin use decreased from 78.2% in 1996 to 37.6% in 2003 (p < 0.0001), while cocaine use increased from 4.1% in 1996 to 30.1% in 2003 (p < 0.0001). In 2003, any use of cocaine was reported by 43.1% of new cases as compared to 38.9% taking heroin, 36.8% cannabis and 5.3% other substances, 41.9% using more than one substance. In 2003, 37.7% of new patients were referred to treatment by the police as compared to 10.4% in 1996. Conclusions: Heroin use has been replaced by cocaine among people coming to treatment centres for the first time. The main mode of access to treatment of new cocaine and cannabis users occurred through mandatory referral by the police. Routine surveillance systems of treatment demand are essential to monitor temporal trends of patterns of drug use in order to plan proper treatment strategies.
Dual Diagnosis in an Inpatient Drug-Abuse Detoxification Unit
Authors: Nocon Agnes , Bergé Daniel , Astals Mónica , Martín-Santos Rocío , Torrens Marta
Published: September 2007

In Spain, detoxification in general hospitals plays an important role in the medical care of patients. We aim to provide clinicians with information on the prevalence and correlates of psychiatric co-morbidity in drug abusers in detoxification. A sample of 115 substance-abuse inpatients (mean age 31.9 ± 6.4 years) in a Detoxification Unit of a general university hospital was studied using the Spanish version of the PRISM. Most of the patients had multiple dependence diagnoses and co-morbid axis I or axis II psychiatric disorders. Patients with dual diagnosis showed lower psychosocial functioning than patients without co-morbidity and more dependence diagnoses due to cannabis and sedatives. A total of 80% of the patients successfully completed the detoxification process. The present results enhance the value of detoxification in a general hospital as a first step of the overall treatment strategy.
Hepatitis C Treatment of Opioid Dependants Receiving Maintenance Treatment: Results of a Norwegian Pilot Study
Authors: Krook Aud L. , Stokka Dorthe , Heger Bernt , Nygaard Egil
Published: September 2007

Background: Many physicians are still skeptic to treat opioid dependants, with or without maintenance treatment, for hepatitis C (HCV) because of concerns about psychiatric comorbidity, stability and adherence. In Norway, there are about 3,500 patients participating in the restrictive medication-assisted rehabilitation (LAR) programs in which all patients are given methadone or buprenorphine maintenance therapy. This study was undertaken to determine whether HCV combination therapy with pegylated interferon α-2a plus ribavirin is feasible, efficient and safe in this patient group. Method: Seventeen patients with HCV genotype 3a were treated for 24 weeks. To optimize compliance, the treatment was given from a department of infectious diseases in cooperation with an LAR center. All injections were given in the LAR center and the patients were given psychosocial support. Results: The compliance was 100%. All responded to the therapy and 16 (94%) were sustained responders. Discussion/Conclusion: This study indicates that compliance and treatment outcome of opioid dependants on methadone or buprenorphine maintenance after 24 weeks of HCV treatment corresponds to that for non-dependants if extra support is given. The treatment should be undertaken in collaboration with specialists in addiction medicine, hepatology and infectious diseases.
Antipsychotic Drug Treatment of Schizophrenic Patients with Substance Abuse Disorders
Authors: San Luis , Arranz Belen , Martinez-Raga Jose
Published: September 2007

Background/Aim: In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature. Methods: A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: ‘schizophrenia’, ‘substance use disorder’ and ‘antipsychotics’. Results: While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder. Conclusion: In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.
Social Regulation of Neurogenesis in Teleosts
Authors: Sørensen Christina , Øverli Øyvind , Summers Cliff H. , Nilsson Göran E.
Published: September 2007

Salmonid fishes such as the rainbow trout (Oncorhynchus mykiss) are frequently used to study behavioral and neuroendocrine effects of socially induced stress. A predictable aggressive response to territorial intrusion, a well described neuroanatomy, and many essential similarities in the stress response in fishes and other vertebrates are among the advantages of this comparative model. One conspicuous difference when compared to mammals, however, is that in telost fish and other non-mammalian vertebrates, neurogenesis persists into adulthood to a much higher degree. Very little is known about the functional significance of individual differences in the rate of brain cell proliferation in fish, or whether structural changes in the fish brain are influenced by the social environment. In this paper we discuss the observation that brain cell proliferation is reduced in subordinate fish, focusing in particular on whether such individual variation reflects a difference in coping style or is indeed a response to social interactions.
Behavioral Diversity and Neurochemical Plasticity: Selection of Stress Coping Strategies That Define Social Status
Authors: Korzan Wayne J. , Summers Cliff H.
Published: September 2007

Social interactions include a variety of stimulating but challenging factors that are the basis for strategies that allow individuals to cope with novel or familiar stressful situations. Evolutionarily conserved strategies have been identified that reflect specific behavioral and physiological identities. In this review we discuss a unique model for social stress in the lizard Anolis carolinensis, which has characteristics amenable to an investigation of individual differences in behavioral responses via central and sympathetic neurochemical adaptation. Profiles of proactive and reactive phenotypes of male A. carolinensis are relatively stable, yet retain limited flexibility that allows for the development of the social system over time. For male A. carolinensis, the celerity of social signal expression and response translate into future social standing. In addition, proactive aggressive, courtship, and feeding behaviors also predict social rank, but are not as important as prior interactions and memories of previous opponents to modify behavioral output and affect social status. The central neurotransmitters dopamine and serotonin, and the endocrine stress axis (HPA) appear to be the fundamental link to adaptive stress coping strategies during social interactions. Only small adaptations to these neural and endocrine systems are necessary to produce the variability measured in behavioral responses to stressful social interactions. These neuroendocrine factors are also manifest in responses to other stimuli and form the basis of heritable strategies for coping with stress.
Stress, Aggression, and Puberty: Neuroendocrine Correlates of the Development of Agonistic Behavior in Golden Hamsters
Authors: Wommack Joel C. , Delville Yvon
Published: September 2007

During puberty, agonistic behaviors undergo significant transitions. In golden hamsters, puberty is marked by a transition from play fighting to adult aggression. During early puberty, male golden hamsters perform play-fighting attacks. This response type is gradually replaced by adult attacks over the course of puberty. Interestingly, this behavioral transition does not appear to be controlled by changes in gonadal steroids. Instead, the shift from play fighting to adult aggression in male golden hamsters is driven by pubertal changes in glucocorticoid levels. Specifically, the transition from play fighting to adult aggression coincides with developmental increases in glucocorticoid levels, and external manipulations such as social stress or treatment with corticosteroid receptor agonists accelerate this behavioral shift. Moreover, the consequences of social stress differ greatly between juvenile and adult male golden hamsters. Although a single defeat during adulthood causes severe and long lasting behavioral and neuroendocrine consequences, socially subjugated juveniles show only transient behavioral effects. As such, it is likely that pubertal changes in the HPA axis are not only linked to the maturation of offensive responses but also determine the consequences of social stress. Combined, these studies in golden hamsters provide a novel mechanism for the development of agonistic behavior and suggest that age related differences in behavioral plasticity are mediated by the development of the HPA axis.
Intermittent Pressure Decreases Human Keratinocyte Proliferation in vitro
Authors: Nasca Maria R. , Shih Alan T. , West Dennis P. , Martinez Wanda M. , Micali Giuseppe , Landsman Adam S.
Published: September 2007

Background: The aim of this study was to investigate the correlation between pressure changes and keratinocyte proliferation by determining whether keratinocytes exposed to altered mechanical pressures would proliferate at different rates compared to control cells not subjected to pressure changes. Methods: Tissue culture flasks of human keratinocytes plated at an approximate density of 15,000 cells/cm2 undergoing an intermittent cyclic pressure of 362 mm Hg at a frequency of 2.28 or 5.16 cycles/min (0.038 or 0.086 Hz) for 8 h were compared to control flasks grown at ambient room pressure. An in-line pressure transducer was used to monitor and adjust pressure within the cell chambers, using a solenoid valve. A thymidine incorporation assay assessed the amount of cell proliferation in each set of experiments. Results: Differences in proliferation between keratinocytes subjected to cyclic pressure changes and control cells were found to be statistically significant (p < 0.05) in 4 out of 5 proliferation assays. Also, a higher frequency of pressure changes consistently generated a reduced proliferation rate compared to that seen in cells exposed to a lower frequency of pressure changes. Conclusion: These data indicate that keratinocytes undergoing intermittent pressure changes exhibit decreased proliferation rates compared to controls. Furthermore, an increased frequency rate seems to have a greater effect on proliferation than low-frequency rate pressure changes, suggesting that the stress caused by frequently changed pressure may play a greater role in reducing keratinocyte proliferation than the actual magnitude of load applied to the cells. Our results support the current treatment protocol of reducing speed and duration of walking on the site of the wound to promote healing of foot ulcers.
Where Does the First Lateral Pelvic Lymph Node Receive Drainage from?
Authors: Kawahara Hidejiro , Nimura Hiroshi , Watanabe Kazuhiro , Kobayashi Tetsuya , Kashiwagi Hideyuki , Yanaga Katsuhiko
Published: September 2007

Background: Lateral pelvic lymph node dissection (LPLD) in the treatment of rectal cancer has risks and benefits. Avoidance of unnecessary LPLD is important, however, preoperative and/or intraoperative accurate detection of lateral lymph node metastases have not been established. If the lateral lymph node to which the fluid first spread from the primary lower rectal cancer is detected accurately, it may guide the need for LPLD and may assist in avoiding unnecessary dissection. Methods: A total of 14 patients with T3 lower rectal cancer were evaluated to locate the lymph nodes through which indocyanine green (ICG) reached the lymphatics. After ICG was injected into the lower rectum via an endoscope preoperatively, total mesorectal excision was first performed, and LPLD was performed with infrared ray electronic endoscopy (IREE) to assess the degree of retention of ICG in each regional lymph node. Results: Drainage of ICG to lateral pelvic lymph nodes was observed in 6 of 14 patients (43%). All ICG-containing lymph nodes were detected by IREE. When present, lateral pelvic wall lymph node drainage was limited exclusively to the peri-internal iliac artery nodes. No obturator nodes were involved. Conclusion: The first lateral lymph node that receives lymphatic drainage from lower rectal cancer is located around the internal iliac arteries.
Chyle Leakage and Early Enteral Feeding following Pancreatico-Duodenectomy: Management Options
Authors: Malik H.Z. , Crozier J. , Murray L. , Carter R.
Published: September 2007

Background: Chyle leaks are a rare complication following abdominal surgery. The aim of this study is to describe the management of chyle leaks following surgery for pancreatico-duodenal malignancy. Methods: Data were collated from a consecutive series of 105 patients who had undergone a pancreatico-duodenectomy for malignancy. From this cohort, patients who developed significant chyle leaks, defined as drainage of more than 600 ml of amylase-poor chylous fluid per day, were identified and their management reviewed. Results: A total of 7 (6.7%) patients with significant chyle leaks were identified. All but one of the chyle leaks were identified between the 5th and 9th post-operative day. Early restoration of enteral feeding appeared to increase the incidence of chyle leak. Six of the 7 patients were successfully treated conservatively with total parenteral nutrition and after a median of 7.5 days the chyle leak had resolved. One patient required a peritoneovenous shunt for chylous ascites. Conclusion: This study has described a high incidence of chyle leak among patients undergoing surgery for pancreatico-duodenal malignancy. Early introduction of enteral feed may encourage development. However, patients who develop an abdominal chyle leak remain clinically well and the leak can be managed relatively easily with parenteral nutrition.
Implementation of a Fast-Track Perioperative Care Program: What Are the Difficulties?
Authors: Polle Sebastiaan W. , Wind Jan , Fuhring Jan W. , Hofland Jan , Gouma Dirk J. , Bemelman Willem A.
Published: September 2007

Background: To evaluate the feasibility of a fast-track (FT) program and it’s effect on postoperative recovery. Methods: All patients, scheduled for elective segmental colorectal resection were treated in a FT program (FT group). Data were compared to a control group operated for elective colorectal resections and treated in a traditional care program (TC group). Data from the FT group were collected prospectively, data from the TC group retrospectively. Outcome parameters included the number of successfully applied FT modalities, patient satisfaction, morbidity rate, re-operation rate, primary (PHS) and total hospital stay (THS), and readmission rate. Results: One-hundred and seven patients were included (55 FT group vs. 52 TC group). The groups were comparable for patient characteristics such as age and cr-POSSUM score (p = 0.22 and p = 0.40). An average of 7.4 of 13 predefined FT modalities were successfully achieved per patient. Patient satisfaction was comparable (p = 0.84). Seven versus 5 patients required a re-operation in the FT and TC groups, respectively (p = 0.52). Morbidity rate was comparable (n = 16 vs. 15, p = 0.83). Median PHS was 4.0 vs. 6.0 days and median THS was 4.0 vs. 6.5 days in the FT and TC groups (p < 0.01 and p < 0.03, respectively). Six vs. 3 patients were re-admitted in the FT and TC groups, respectively (p = 0.49). Conclusion: Implementation of all FT modalities was difficult since a rather low number of pre-defined FT modalities was effectively realized. Despite incomplete implementation, PHS and THS were shorter in the FT group without affecting patient satisfaction.
Do Elderly Cancer Patients Achieve an Adequate Dose Intensity in Common Clinical Practice?
Authors: Luciani A. , Marussi D. , Ascione G. , Caldiera S. , Ferrari D. , Oldani S. , Uziel L. , Zonato S. , Foa P.
Published: September 2007

Background: Elderly patients rarely receive adequate dose intensity (DI) using conventional regimens. Possible causes are improper patient assessment, the chemotherapy (CT) regimen chosen, the number and severity of comorbidities, patient compliance and physician experience. To explore this issue, DI was retrospectively analyzed in elderly patients treated with conventional CT regimens for advanced solid cancer. Patients and Methods: Patients ≧69 years were evaluated. All patients had metastatic solid tumors. Comorbidities, performance status (PS), toxicities, number of CT cycles, dose reduction and discontinuation of treatment were recorded. Relative DI (RDI) was calculated and regressed against these parameters. Results: 108 patients were eligible. The most frequent diagnoses were: lung, head-and-neck and colorectal cancer. In 48 patients (44%), their initially scheduled treatment was modified. Mean RDI was 79% (range 19–100%, SD 20.6). Grade 3/4 non-hematological and hematological toxicity occurred in 27 (35/130) and 8% of patients (11/130), respectively. In regression analysis, RDI was significantly associated with hematological toxicity. RDI affected response rate but not overall survival. Conclusions: RDI is significantly affected by toxicity. These data suggest the importance of the treatment schedule and patient selection as predictorsof adequate treatment. Some non-ratable variables, however, might also play a role regarding the dose intensity delivered.