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Combination of targeted delivery and controlled release is a powerful technique for cancer treatment. In this paper, we describe the design, synthesis, structure validation and biological properties of targeted and non-targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-docetaxel conjugates. Docetaxel (DTX) was conjugated to HPMA copolymer via a tetrapeptide spacer (-GFLG-). 3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA) was used as the targeting moiety to actively deliver DTX for treatment of Prostate-Specific Membrane Antigen (PSMA) expressing prostate cancer. Short and long spacer DUPA monomers were prepared, and four HPMA copolymer--DTX conjugates (non-targeted, two targeted with short spacer of different molecular weight and targeted with long spacer) were prepared via Reversible Addition-Fragmentation Chain Transfer (RAFT) copolymerization. Following confirmation of PSMA expression on C4-2 cell line, the DTX conjugates' in vitro cytotoxicity was tested against C4-2 tumor cells and their anticancer efficacies were assessed in nude mice bearing s.c. human prostate adenocarcinoma C4-2 xenografts. The in vivo results show that the spacer length between targeting moieties and HPMA copolymer backbone can significantly affect the treatment efficacy of DTX conjugates against C4-2 tumor bearing nu/nu mice. Moreover, histological analysis indicated that the DUPA-targeted DTX conjugate with longer spacer had no toxicity in major organs of treated mice.

Multiblock, high molecular weight, linear, backbone degradable HPMA copolymer-prostaglandin E1 (PGE1) conjugate has been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA), which contains an enzymatically degradable oligopeptide sequence flanked by two dithiobenzoate groups, followed by postpolymerization aminolysis and thiol-ene chain extension. The multiblock conjugate contains Asp8 as the bone targeting moiety and enzymatically degradable bonds in the polymer backbone; in vivo degradation produces cleavage products that are below the renal threshold. Using an ovariectomized (OVX) rat model, the accumulation in bone and efficacy to promote bone formation was evaluated; low molecular weight conjugates served as control. The results indicated a higher accumulation in bone, greater enhancement of bone density, and higher plasma osteocalcin levels for the backbone degradable conjugate., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The performance and safety of current antineoplastic agents, particularly water-insoluble drugs, are still far from satisfactory. For example, the currently widely used Cremophor EL®-based paclitaxel (PTX) formulation exhibits pharmacokinetic concerns and severe side effects. Thus, the concept of a biodegradable polymeric drug-delivery system, which can significantly improve therapeutic efficacy and reduce side effects is advocated. The present work aims to develop a new-generation of long-circulating, biodegradable carriers for effective delivery of PTX. First, a multiblock backbone biodegradable N-(2-hydroxypropyl)methacrylamide(HPMA) copolymer-PTX conjugate (mP-PTX) with molecular weight (Mw) of 335 kDa was synthesized by RAFT (reversible addition-fragmentation chain transfer) copolymerization, followed by chain extension. In vitro studies on human ovarian carcinoma A2780 cells were carried out to investigate the cytotoxicity of free PTX, HPMA copolymer-PTX conjugate with Mw of 48 kDa (P-PTX), and mP-PTX. The experiments demonstrated that mP-PTX has a similar cytotoxic effect against A2780 cells as free PTX and P-PTX. To further compare the behavior of this new biodegradable conjugate (mP-PTX) with free PTX and P-PTX in vivo evaluation was performed using female nu/nu mice bearing orthotopic A2780 ovarian tumors. Pharmacokinetics study showed that high Mw mP-PTX was cleared more slowly from the blood than commercial PTX formulation and low Mw P-PTX. SPECT/CT imaging and biodistribution studies demonstrated biodegradability as well as elimination of mP-PTX from the body. The tumors in the mP-PTX treated group grew more slowly than those treated with saline, free PTX, and P-PTX (single dose at 20 mg PTX/kg equivalent). Moreover, mice treated with mP-PTX had no obvious ascites and body-weight loss. Histological analysis indicated that mP-PTX had no toxicity in liver and spleen, but induced massive cell death in the tumor. In summary, this biodegradable drug delivery system has a great potential to improve performance and safety of current antineoplastic agents., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Backbone degradable, linear, multiblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (DOX) conjugates are synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization followed by chain extension via thiol-ene click reaction. The examination of molecular-weight-dependent antitumor activity toward human ovarian A2780/AD carcinoma in nude mice reveals enhanced activity of multiblock, second-generation, higher molecular weight conjugates when compared with traditional HPMA copolymer-DOX conjugates. The examination of body weight changes during treatment indicates the absence of non-specific adverse effects., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biodistribution, pharmacokinetics, and efficacy of prostate-cancer-targeted HPMA copolymer/DTX conjugates are evaluated in nude mice bearing prostate cancer C4-2 xenografts. PSMA-specific monoclonal antibodies 3F/11 are used as the targeting moiety. Control conjugates tumor accumulation to total background organs (heart, lung, kidney, liver, spleen and blood) accumulation increase substantially with time for the targeted conjugate, and the ratio at 48 h is 7-fold higher than that at 6 h. Preliminary evaluation of the efficacy of the conjugates in vivo show tumor growth inhibition for all HPMA copolymer/DTX conjugates.

Celiac disease (CD) is a chronic intestinal disorder of public health concern caused by gluten ingestion in sensitive individuals. Gluten is a protein found not only in gluten-containing food but also as normal component of drugs and dietary supplements. Detection of gluten in dietary supplements is a very important task required for establishing their gluten status, which is highly important for the safety of products consumed by CD and gluten-sensitive patients. In this paper, we investigated the presence of gluten in twenty one common dietary supplements from the national market using the immunochromatographic assay. This visual assay proved to be an efficient rapid tool for gluten screening as an alternative to the ELISA techniques. The results have shown the presence of gluten in 23.8% of the investigated samples (vitamins, minerals, plant extracts, probiotics supplements, lactoferrin, propolis supplements). The results provide information which may contribute to the completion of the existing lists of gluten-free pharmaceuticals. It is known that for CD patients obtaining accurate information about the gluten content of a particular item is a difficult and time-consuming process.

Sulfidic mine tailings have to be classified as one of the major source of hazardous materials leading to water contamination. This study highlights the processes leading to sulfide oxidation and acid mine drainage (AMD) formation in the active stage of two tailings impoundments located in the southern part of the Apuseni Mountains, in Romania, a well-known region for its long-term gold-silver and metal mining activity. Sampling was undertaken when both impoundments were still in operation in order to assess their actual stage of oxidation and long-term behavior in terms of the potential for acid mine drainage generation. Both tailings have high potential for AMD formation (2.5 and 3.7 wt.% of pyrite equivalent, respectively) with lesser amount of carbonates (5.6 and 3.6 wt.% of calcite equivalent) as neutralization potential (ABA=-55.6 and -85.1 tCaCO(3)/1000 t ) and showed clear signs of sulfide oxidation yet during operation. Sequential extraction results indicate a stronger enrichment and mobility of elements in the oxidized tailings: Fe as Fe(III) oxy-hydroxides and oxides (transformation from sulfide minerals, leaching in oxidation zone), Ca mainly in water soluble and exchangeable form where gypsum and calcite are dissolved and higher mobility of Cu for Ribita and Pb for Mialu. Two processes leading to the formation of mine drainage at this stage could be highlighted (1) a neutral Fe(II) plume forming in the impoundment with ferrihydrite precipitation at its outcrop and (2) acid mine drainage seeping in the unsaturated zone of the active dam, leading to the formation of schwertmannite at its outcrop., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background, Aim and Scope: In the region of the Apuseni Mountains, part of the Western Carpathians in Romania, metal mining activities have a long-standing tradition. These mining industries created a clearly beneficial economic development in the region. But their activities also caused impairments to the environment, such as acid mine drainage (AMD) resulting in long-lasting heavy metal pollution of waters and sediments. The study, established in the context of the ESTROM programme, investigated the impact of metal mining activities both from environmental and socioeconomic perspectives and tried to incorporate the results of the two approaches into an integrated proposition for mitigation of mining-related issues., Study Site: The small Certej catchment, situated in the Southern Apuseni Mountains, covers an area of 78 km(2). About 4,500 inhabitants are living in the basin, in which metal mining was the main economic sector. An open pit and several abandoned underground mines are producing heavy metal-loaded acidic water that is discharged untreated into the main river. The solid wastes of mineral processing plants were deposited in several dumps and tailings impoundment embodying the acidic water-producing mineral pyrite., Methods: The natural science team collected samples from surface waters, drinking water from dug wells and from groundwater. Filtered and total heavy metals, both after enrichment, and major cations were analysed by inductively coupled plasma optical emission spectroscopy (ICP-OES). Major anions in waters, measured by ion chromatography, alkalinity and acidity were determined by titration. Solid samples were taken from river sediments and from the largest tailings dam. The latter were characterised by X-ray fluorescence and X-ray diffraction. Heavy metals in sediments were analysed after digestion. Simultaneously, the socioeconomic team performed a household survey to evaluate the perception of people related to the river and drinking water pollution by way of a logistic regression analysis., Results and Discussion: The inputs of acid mine waters drastically increased filtered heavy metal concentrations in the Certej River, e.g. Zn up to 130 mg L(-1), Fe 100 mg L(-1), Cu 2.9 mg L(-1), Cd 1.4 mg L(-1) as well as those of SO(4) up to 2.2 g L(-1). In addition, river water became acidic with pH values of pH 3. Concentrations of pollutant decreased slightly downstream due to dilution by waters from tributaries. Metal concentrations measured at headwater stations reflect background values. They fell in the range of the environmental quality standards proposed in the EU Water Framework Directive for dissolved heavy metals. The outflow of the large tailing impoundment and the groundwater downstream from two tailings dams exhibited the first sign of AMD, but they still had alkalinity. Most dug wells analysed delivered a drinking water that exhibited no sign of AMD pollution, although these wells were a distance of 7 to 25 m from the contaminated river. It seems that the Certej River does not infiltrate significantly into the groundwater. Pyrite was identified as the main sulphide mineral in the tailings dam that produces acidity and with calcite representing the AMD-neutralising mineral. The acid-base accounting proved that the potential acid-neutralising capacity in the solid phases would not be sufficient to prevent the production of acidic water in the future. Therefore, the open pits and mine waste deposits have to be seen as the sources for AMD at the present time, with a high long-term potential to produce even more AMD in the future. The socioeconomic study showed that mining provided the major source of income. Over 45% of the households were partly or completely reliant on financial compensations as a result of mine closure. Unemployment was considered by the majority of the interviewed persons as the main cause of social problems in the area. The estimation of the explanatory factors by the logistic regression analysis revealed that education, household income, pollution conditions during the last years and familiarity with environmental problems were the main predictors influencing peoples' opinion concerning whether the main river is strongly polluted. This model enabled one to predict correctly 77% of the observations reported. For the drinking water quality model, three predictors were relevant and they explained 66% of the observations., Conclusions: Coupling the findings from the natural science and socioeconomic approaches, we may conclude that the impact of mining on the Certej River water is high, while drinking water in wells is not significantly affected. The perceptions of the respondents to pollution were to a large extent consistent with the measured results., Recommendations and Perspectives: The results of the study can be used by various stakeholders, mainly the mining company and local municipalities, in order to integrate them in their post-mining measures, thereby making them aware of the potential long-term impact of mining on the environment and on human health as well as on the local economy.

Mining-contaminated sites and the affected communities at risk are important issues on the agenda of both researchers and policy makers, particularly in the former communist block countries in Eastern Europe. Integrated analyses and expert based assessments concerning mining affected areas are important in providing solid policy guidelines for environmental and social risk management and mitigation. Based on a survey for 103 households conducted in a former mining site in the Certej Catchment of the Apuseni Mountains, western Romania, this study assesses local communities' perceptions on the quality of water in their living area. Logistic regression was used to examine peoples' perception on the quality of the main river water and of the drinking water based on several predictors relating to social and economic conditions. The results from the perception analysis were then compared with the measurements of heavy metal contamination of the main river and drinking water undertaken in the same study area. The findings indicate that perception and measurement results for the water quality in the Certej Catchment are convergent, suggesting an obvious risk that mining activities pose on the surface water. However, the perception on drinking water quality was little predicted by the regression model and does not seem to be so much related to mining as to other explanatory factors, such as special mineralogy of rock and soils or improper water treatment infrastructure, facts suggested by the measurements of the contaminants. Discussion about the implications of these joint findings for risk mitigation policies completes this article.

Bone-targeting N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-PGE(1) conjugates, containing cathepsin K sensitive spacers, were incubated with induced osteoclasts and osteoblasts, their precursors, and control non-skeletal cells. The release of PGE(1) was monitored by an HPLC assay. In both murine and human cell lines, osteoclasts appeared to be the most active cells in the cleavage (PGE(1) release). Incubation with osteoblasts also resulted in fast PGE(1) release, whereas precursor and control cells released PGE(1) with a substantially slower rate than bone cells (apparently through ester bond cleavage). Experiments in the presence of inhibitors revealed that other enzymes, in addition to cathepsin K, were participating in the cleavage of the conjugate. Confocal fluorescence studies exposed internalization of the conjugate by endocytosis with ultimate localization in the lysosomal/endosomal compartment.

The biodistribution and pharmacokinetics of bone-targeting N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-alendronate conjugates were evaluated following intravenous administration of radioiodinated conjugates to young healthy BALB/c mice. The synthesis of a polymerizable and cathepsin K cleavable alendronate derivative, N-methacryloylglycylglycylprolylnorleucylalendronate, enabled the preparation of HPMA copolymer-alendronate conjugates with varying composition. Using the RAFT (reversible addition-fragmentation chain transfer) polymerization technique, four conjugates with different molecular weight and alendronate content and two control HPMA copolymers (without alendronate) with different molecular weight were prepared. The results of biodistribution studies in mice demonstrated a strong binding capacity of alendronate-targeted HPMA copolymer conjugates to bone. Conjugates with low (1.5 mol%) alendronate content exhibited a similar bone deposition capacity as conjugates containing 8.5 mol % of alendronate. The molecular weight was an important factor in the biodistribution of the HPMA copolymer conjugates. More conjugate structures need to be evaluated, but the data suggest that medium molecular weights (50-100 kDa) might be effective drug carriers for bone delivery.

Acral myxoinflammatory fibroblastic sarcoma (AMIFS) is a low-grade sarcoma that presents mostly in distal extremities of middle-aged patients. The clinicopathologic features, immunohistochemical profile and follow-up data of five cases (three men and two women; age 39-65 years) are presented. The tumors presented as a slow-growing, poorly circumscribed, subcutaneous masses in the hands (three), foot (one) and calf (one), with dermal involvement in two cases. They had myxoid and hyaline stroma with dense acute and chronic inflammation. Spindle cells, large bizarre ganglion-like cells and multivacuolated cells were seen. Variable reactivity in lesional cells were noted for vimentin, Alpha-1-antitrypsin (A1AT), factor XIIIa, CD68, CD95, CD117, Alpha-1-antichymotrypsin (A1ACT), CD34, AE1/3, S-100 protein, EBER, CD63 and CD15. MIB-1 showed 5-30% nuclear labeling. They were negative for cytokeratin AE1/3, smooth muscle actin, CD30, ALK-1, EMA, desmin, CMV, HMB-45 and Melan-A. Follow up ranged from 2 weeks to 95 months (mean 54). One patient was lost to follow up; three underwent excision and one patient had below the knee amputation. Two patients developed metastases (one died of disease), and two patients are alive without evidence of disease. AMIFS are rare tumors that may involve joints and tendons leading to clinical diagnosis of ganglion cyst or tenosynovitis.

Objective: To evaluate the efficacy of cognitive-behavioral interventions (CBIs) for improving the mental health and immune functioning of people living with HIV (PLWH)., Design: Comprehensive searches of electronic databases from 1988 to 2005, hand searches of journals, reference lists of articles, and contacts with researchers. Meta-analytic approaches were used in synthesizing findings., Main Outcome Measures: Intervention effects on symptoms of depression, anxiety, and anger, stress, and CD4 cell counts were assessed., Results: Data from 15 controlled trials were analyzed. Significant intervention effects were observed for improving symptoms of depression (d = 0.33), anxiety (d = 0.30), anger (d = 1.00), and stress (d = 0.43). There is limited evidence suggesting intervention effects on CD4 cell counts (d = 0.08). The aggregated effect size estimates for depression and anxiety were statistically significant in trials that provided stress management skills training and had more than 10 intervention sessions., Conclusion: CBIs are efficacious in improving various psychological states of PLWH. Future research should examine the relationship among interventions, psychological states, medication adherence, and immune functions, and identify other relevant factors associated with intervention effects.

Objectives: Interventions targeting sexually transmitted disease (STD) clinic patients provide an important opportunity to modify high-risk sex behaviors related to HIV/STD transmission. Identifying efficacious interventions for blacks and Hispanics is urgently needed because these 2 groups are disproportionately affected by the HIV/STD epidemics., Goal: This meta-analysis evaluates the efficacy of behavioral interventions in reducing unprotected sex and incident STD among black and Hispanic STD clinic patients., Study Design: Comprehensive searches, including electronic databases (1988-2004), hand searches of journals (January 2004 to June 2005), reference lists of articles, and contacts with researchers, identified 18 randomized, controlled trials meeting the selection criteria., Results: Interventions significantly reduced unprotected sex (odds ratio [OR] = 0.77; 95% confidence interval [CI] = 0.68-0.87; 14 trials; N = 11,590) and incident STD (OR = 0.85; 95% CI = 0.73-0.998; 13 trials; N = 16,172)., Conclusions: Behavioral interventions provide an efficacious means of HIV/STD prevention for blacks and Hispanics who attend STD clinics.

Objectives: The Centers for Disease Control and Prevention's HIV/AIDS Prevention Research Synthesis Team conducted a systematic review of US-based HIV behavioral intervention research literature from 2000 through 2004 to identify interventions demonstrating best evidence of efficacy for reducing HIV risk., Methods: Standard systematic review methods were used. Each eligible study was reviewed on the basis of Prevention Research Synthesis Team efficacy criteria that focused on 3 domains: study design, implementation and analysis, and strength of evidence., Results: Eighteen interventions met the criteria for best evidence. Four targeted HIV-positive individuals. Of those targeting populations at risk for HIV, 4 targeted drug users, 6 targeted adults at risk because of heterosexual behaviors only, 2 targeted men who have sex with men, and 2 targeted youths at high risk. Eight interventions focused on women, and 13 had study samples with more than 50% minority participants. Significant intervention effects included increased condom use and reductions in unprotected sexual intercourse, number of sexual partners, injection drug use or needle sharing, and newly acquired sexually transmitted infections., Conclusions: Most of the best-evidence interventions are directly applicable for populations in greatest need of effective prevention programs; however, important gaps still exist.

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125I-labeled bone-targeted and control (nontargeted) HPMA copolymers were administered intravenously to mice, and their distribution to different organs and tissues was followed using gamma counter and single photon emission computed tomography (SPECT). Both the invasive and noninvasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp8) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (Mw of 24, 46, and 96 kDa) of HPMA copolymer-D-Asp8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone selectivity. A higher content of bone-targeting moiety (D-Asp8) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.

Purpose: To study the accumulation of macromolecules into the arthritic joints and the possible applications of such phenomenon., Methods: The accumulation of plasma albumin in the joints of adjuvant-induced arthritis (AIA) rat model was first visualized with Evans blue injection. A N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer contrast agent was then synthesized and injected into the AIA rats to allow qualitative examination of biodistribution and pharmacokinetics of the injected macromolecule with magnetic resonance imaging (MRI). Vital organs and the diseased joints were isolated and examined histologically to correlate with the MRI findings., Results: Deep blue color developed around the arthritic joints of the AIA rat a few hours after the injection of Evans blue. MR imaging of the AIA rats injected with polymer contrast agent demonstrated a gradual but very strong accumulation of the injected polymer in the arthritic joints, which lasted for 1-2 days. Observed differences in the concentration of the injected polymer in the joints correlated with disease severity as assessed histologically., Conclusions: Profound arthrotropism of macromolecules in the AIA rat model was demonstrated with various imaging tools. These observations should help in the conceptual and practical design of novel macromolecular delivery systems for the imaging and treatment of rheumatoid arthritis.

This paper is a follow-up of earlier findings by the Kagera AIDS Research Project (KARP), which documented declining trends in the prevalence and incidence of HIV infection in the Kagera region of Tanzania. The paper examines socio-cultural and sexual behavioral changes as possible determinants of the observed declining trends in Bukoba, the largest urban area of the region. The study used in-depth interviews, focus group discussions, field observations and ethnographic assessments to collect the required data. The findings suggest that since the initial years of the epidemic there have been significant changes in sexual behaviors, norms, values, and customs that are considered high-risk for HIV transmission. The findings show an increase in condom use, abstinence, zero grazing (sticking to one sexual partner) and uptake of voluntary HIV testing while traditional practices such as polygamy, widow inheritance, excessive alcohol consumption, and sexual networking are declining. We suggest that these changes are partly a result of the severity of the epidemic itself in the study area, and interventions that have been carried out in this area since 1987. The major interventions have included health education, the distribution of condoms, AIDS education in schools, voluntary HIV counseling and testing. These are encouraging findings that give hope and we believe that other places within Tanzania and other countries experiencing a severe AIDS crisis have much to learn from this experience. However, changes in norms and behavior are vulnerable; people in Kagera are still at risk and there is a need for continued intervention together with monitoring of the direction of the epidemic., (Copyright 2003 Elsevier Ltd.)

Nephrogenic fibrosing dermopathy (NFD) is a rare and recently recognized sclerosing skin disorder of unknown etiology. Reported cases have occurred in patients with chronic renal failure, with or without renal replacement therapy. All previous cases have been reported in older adult patients. We describe two pediatric patients who recently developed this condition and review the existing literature for NFD. Our patients included an 8-year-old boy on peritoneal dialysis with no prior renal transplant and a 19-year-old boy on hemodialysis with a history of previous failed renal transplants. We speculate that the recent emergence of this condition and occurrence in patients with chronic renal failure suggest an association with some newer pharmacological agent that has recently come into wide use. Since both our patients also had previously experienced large vessel thrombosis, hypercoagulable states may also be implicated.

Four polymeric bone-targeting conjugates were synthesized based on poly(ethylene glycol) (PEG, two conjugates) and poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA, two conjugates). The well-known bone-targeting compounds, alendronate and aspartic acid peptide, were used as bone-targeting moieties. Fluorescein isothiocyanate (FITC) was attached to the conjugates as a model drug for detection purposes. The bone-targeting potential of these conjugates was tested in vitro with hydroxyapatite (HA) and in mice. The data obtained indicated that these novel delivery systems could specifically accumulate in the bone tissue.

Experiments were conducted to determine if hypotensive responses to chicken cardiac hypotensive extract (CHE) or synthetic rat atrial natriuretic peptide (ANP) are affected by dietary sodium. The CHE was significantly more hypotensive in chickens fed high-sodium diets than in chickens fed low-sodium diets. Atrial natriuretic peptide was equally hypotensive in both groups. Experiments were also conducted to determine whether CHE inhibits the hypertensive response to arginine vasotocin (AVT), the avian antidiuretic hormone. The acute hypertensive response to AVT was inhibited by CHE; and CHE reversed the AVT-induced increase in the baseline mean arterial blood pressure.