bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular and cerebrovascular responses to acute isocapnic and poikilocapnic hypoxia in humans
Authors: Steinback Craig D. , Poulin Marc J.
Published: October 2007

We examined the cardiovascular and cerebrovascular responses to acute isocapnic (IH) and poikilocapnic hypoxia (PH) in 10 men (25.7 ± 4.2 yr, mean ± SD). Heart rate (HR), mean arterial pressure (MAP), and mean peak middle cerebral artery blood flow velocity (V̄p) were measured continuously during two randomized protocols of 20 min of step IH and PH (45 Torr). HR was elevated during both IH ( P < 0.01) and PH ( P < 0.01), with no differences observed between conditions. MAP was modestly elevated across all time points during IH but only became elevated after 5 min during PH. During IH, V̄p was elevated from baseline throughout the exposure with a consistent hypoxic sensitivity of ∼0.34 cm·s−1·%desaturation−1( P < 0.05). The V̄p response to PH was biphasic with an initial decrease from baseline occurring at 79 ± 23 s, followed by a subsequent elevation, becoming equivalent to the IH response by 10 min. The nadir of the PH response exhibited a hypoxic sensitivity of −0.24 cm·s−1·%desaturation−1. When expressed in relation to end-tidal Pco2, a sensitivity of −1.08 cm·s−1·Torr−1was calculated, similar to previously reported sensitivities to euoxic hypocapnia. Cerebrovascular resistance (CVR) was not changed during IH. During PH, an initial increase in CVR was observed. However, CVR returned to baseline by 20 min of PH. These data show the cerebrovascular response to PH consists of an early hypocapnia-mediated response, followed by a secondary increase, mediated predominantly by hypoxia.
Outcomes of Nontransplant Potentially Curative Therapy for Early-Stage Hepatocellular Carcinoma in Child-Pugh Stage A Cirrhosis Is Comparable with Liver Transplantation
Authors: Takahashi Shunsuke , Kudo Masatoshi , Chung Hobyung , Inoue Tatsuo , Nagashima Miki , Kitai Satoshi , Tatsumi Chie , Minami Yasunori , Ueshima Kazuomi , Fukunaga Toyokazu , Haji Seiji
Published: October 2007

Background: This study was undertaken to assess the outcome of potentially curative therapy for early-stage hepatocellular carcinoma (HCC) in patients with Child-Pugh stage A cirrhosis as well as to investigate the impact of low-dose interferon (IFN) therapy after curative therapy on survival. Methods: This study retrospectively evaluated clinical outcomes in a cohort of 224 Child-Pugh stage A cirrhotic patients who received either resection (53 cases) or radiofrequency ablation (RFA: 171 cases) for HCC within Milan criteria. Thirty patients were treated with low-dose maintenance IFN therapy after initial curative therapy. The median follow-up period was 36.7 months. Results: The 5-year survival rate of all patients was 74.9%, with similar rates for the resection and RFA groups (70.4 vs. 76.8%; p = 0.561). The 5-year HCC recurrence rate was higher in the RFA group than the resection group (85.3 vs. 73.2%; p = 0.012). The maintenance IFN-treated group maintained their liver function within Child-Pugh stage A for a significantly longer time (median time 36.9 vs. 32.2 months; p = 0.0025). Conclusion: The 5-year outcomes of resection and RFA in patients with Child-Pugh stage A cirrhosis and early stage HCC were comparable with liver transplantation. Low-dose, long-term maintenance IFN therapy after curative therapy was significantly beneficial on survival.
Liver Transplantation for Hepatocellular Carcinoma: Single Nodule with Child-Pugh Class A Sized Less than 3 cm
Authors: Moon Deok-Bog , Lee Sung-Gyu , Hwang Shin
Published: October 2007

Backgrounds/Aims: Hepatic resection (HR) has been the standard therapy for patients with small hepatocellular carcinoma (HCC) with preserved liver function in Child A cirrhosis. However, the underlying cirrhosis is responsible for high recurrence and long-term complications of portal hypertension and liver failure. Currently, liver transplantation (LT) has proven to be a good alternative to HR. We studied to determine whether LT could be an alternative initial therapy or not in HCC patients with less than 3 cm-sized, single nodule with Child A cirrhosis. Methods: From January 1995 to December 2005, there were 100 HR and 17 LT (living donor LT 15, deceased donor LT 2) patients. Clinicopathologic characteristics were reviewed and survival rates between LT and HR groups were compared. The applicability of salvage LT at the time of recurrence was also evaluated. Results: There was no difference in age, sex, etiology and in-hospital mortality between the two groups. LTs were not performed for the patients with preserved liver function, that is, BCLC stage A1. Most initial recurrences after HR occurred in liver (37/39), but only one recurrence after LT occurred in lung. Overall survival differences between LT and HR were not significant. However, disease-free survival after LT and HR were significantly different (p = 0.047). Potential candidates for salvage LT were 37 patients including hepatic failure (n = 10), and its applicability on recurrence was 69.2% (27/39). Conclusion: HR is still a good option for the selected patients because of lower cost and no requirement of donors. However, primary LT can be a treatment of choice for single, small HCC of Child A cirrhosis in the presence of portal hypertension because of excellent disease-free survival.
Liver Transplantation for Solitary Hepatocellular Carcinoma Less than 3 cm in Diameter in Child A Cirrhosis
Authors: Poon Ronnie T.P.
Published: October 2007

Liver transplantation for hepatocellular carcinoma (HCC) is the treatment of choice for patients with unresectable tumors within the Milan criteria associated with Child B or C cirrhosis. Liver transplantation provides the best cure for both the HCC and the underlying cirrhosis. In recent years, some authors have advocated liver transplantation even for resectable early HCC associated with Child A cirrhosis, leading to a controversy of whether resection or transplantation should be the first-line therapy for patients with small HCC in Child A cirrhosis. Recent studies comparing liver resection and transplantation for early HCC demonstrated similar long-term survival of 60–70%, but liver transplantation is associated with a lower tumor recurrence rate. However, the current shortage of deceased donor liver grafts limits the applicability of liver transplantation for HCC. The use of live donor liver transplantation for patients with a small solitary HCC in Child A cirrhosis that is resectable may not be justified ethically because of the potential risk to the donors. Patients put on a transplantation waiting list run a significant risk of tumor progression and dropout, while liver resection is immediately applicable to all. Advocating primary liver transplantation for patients with early HCC associated with compensated cirrhosis will increase the waiting time for transplantation and further increases the chance of dropout. Resection first and salvage transplantation for recurrent tumors or liver failure is an alternative strategy that may reduce the use of liver grafts. However, the long-term survival result of such a strategy compared with primary liver transplantation remains unclear.
Inhibition of the Tyrosine Phosphatase SHP-2 Suppresses Angiogenesis in vitro and in vivo
Authors: Mannell Hanna , Hellwig Nicole , Gloe Torsten , Plank Christian , Sohn Hae-Young , Groesser Leopold , Walzog Barbara , Pohl Ulrich , Krötz Florian
Published: October 2007

Endothelial cell survival is indispensable to maintain endothelial integrity and initiate new vessel formation. We investigated the role of SHP-2 in endothelial cell survival and angiogenesis in vitro as well as in vivo. SHP-2 function in cultured human umbilical vein and human dermal microvascular endothelial cells was inhibited by either silencing the protein expression with antisense-oligodesoxynucleotides or treatment with a pharmacological inhibitor (PtpI IV). SHP-2 inhibition impaired capillary-like structure formation (p < 0.01; n = 8) in vitroas well as new vessel growth ex vivo(p < 0.05; n = 10) and in vivo in the chicken chorioallantoic membrane (p < 0.01, n = 4). Additionally, SHP-2 knock-down abrogated fibroblast growth factor 2 (FGF-2)-dependent endothelial proliferation measured by MTT reduction (p < 0.01; n = 12). The inhibitory effect of SHP-2 knock-down on vessel growth was mediated by increased endothelial apoptosis (annexin V staining, p < 0.05, n = 9), which was associated with reduced FGF-2-induced phosphorylation of phosphatidylinositol 3-kinase (PI3-K), Akt and extracellular regulated kinase 1/2 (ERK1/2) and involved diminished ERK1/2 phosphorylation after PI3-K inhibition (n = 3). These results suggest that SHP-2 regulates endothelial cell survival through PI3-K-Akt and mitogen-activated protein kinase pathways thereby strongly affecting new vessel formation. Thus, SHP-2 exhibits a pivotal role in angiogenesis and may represent an interesting target for therapeutic approaches controlling vessel growth.
Predictors of Early Dialysis Vascular-Access Failure after Thrombolysis
Authors: Crikis Sandra , Lee Darren , Brooks Mark , Power David A. , Ierino Francesco L. , Levidiotis Vicki
Published: October 2007

Background: Vascular-access patency is critical for effective and uninterrupted haemodialysis. Limited literature exists evaluating if a surgical or repeated radiological approach is superior for reocclusion following failure of radiological recanalization. Few consistent early predictors of failure have been identified after radiological intervention for thrombosed vascular access. Methods: 138 patients with thrombosed arteriovenous fistulas or prosthetic grafts treated by radiological intervention, over 10 years, were retrospectively investigated. Reocclusion was treated by either repeated thrombolysis or surgery. Radiological patency rates, after first and second episodes of access thrombosis at 12 months after intervention were analysed. Surgical and radiological patency rates for second access thrombosis were compared. The Cox and logistic regression models were used to identify potential factors associated with reocclusion. Results: In patients who experienced reocclusion within 1 month after radiological intervention, the 3-month repeated radiological patency rate (n = 13) was 38.5%, compared to a 60% surgical patency rate (n = 10), but this did not reach statistical significance. Radiological patency rates after first access thrombosis at 3 and 12 months were 56.6 and 39.5%, respectively. In contrast, radiological patency rates after a second access thrombosis were 51.1 and 24.4%, respectively; a statistical difference in success was not achieved. Native arteriovenous fistulas were 3.23 times as likely to remain patent over 12 months following a first radiological intervention (p < 0.02) and less likely to experience a second reocclusion event (p < 0.01). Anticoagulation was associated with a lower risk of second reocclusion, whilst a history of venous thrombosis was associated with a greater risk (p < 0.02). Conclusion: Surgery achieves superior patency rates compared to repeated radiological interventions and should be considered if reocclusion occurs within a month following radiological thrombolysis.
Oral β-Glucan Protects Kidney against Ischemia/Reperfusion Injury in Rats
Authors: Bayrak Omer , Turgut Faruk , Karatas Omer Faruk , Cimentepe Ersin , Bayrak Reyhan , Catal Ferhat , Atis Omer , Akcay Ali , Unal Dogan
Published: October 2007

Background: Ischemia-reperfusion (I/R) injury is one of the leading causes of acute renal failure. β-(1→3)-Glucans are glucose polymers with a variety of stimulatory effects on the immune system. We designed this study to determine the possible protective effect of the orally administered soluble β-glucan against I/R injury. Methods: 30 rats were randomly divided into 5 experimental groups (control, sham operated, β-glucan, I/R and I/R+β-glucan groups, n = 6 each). β-Glucan was administered orally to 6 rats of the β-glucan and I/R+β-glucan groups. The rats were subjected to bilateral renal ischemia followed by reperfusion in the I/R and I/R+β-glucan groups. All of the rats were then sacrificed and kidney function tests, serum and tissue oxidants and antioxidants were evaluated. Results: The serum urea and cystatin C levels were significantly higher in the I/R group compared to the I/R+β-glucan group (p < 0.01). The serum and tissue antioxidant markers (SOD, GSH-Px) were significantly lower in the I/R group than the I/R+β-glucan group (p < 0.01). The serum oxidant markers (NO and PC) were significantly higher in the I/R group than the I/R+β-glucan group (p < 0.01). Conclusion: Based on the present data, we conclude that increased antioxidants and decreased oxidants modulated by β-glucan attenuated the renal I/R injury.
Neointimal Expression of Rapamycin Receptor FK506-Binding Protein FKBP12: Postinjury Animal and Human In-Stent Restenosis Tissue Characteristics
Authors: Bauriedel Gerhard , Jabs Alexander , Kraemer Stefan , Nickenig Georg , Skowasch Dirk
Published: October 2007

Despite excellent clinical results for sirolimus (rapamycin)-eluting stents, the exact mechanisms of antirestenotic activity and affected cellular targets are incompletely understood. Therefore, we determined the presence and tem- porospatial expression pattern of FKBP12, the primary intracellular receptor of rapamycin, in rat carotid arteries after balloon injury, as well as in human in-stent restenosis and primary stable coronary atheroma. FKBP12 expression was assessed by immunohistochemistry. Rat carotid arteries revealed maximal expression in 57.7 ± 4.0% of neointimal cells at day 7. A large proportion of these FKBP12+ cells showed luminally confined co-expression with dendritic cell markers. Despite a considerably thicker neointima at day 28, presence of FKBP12 decreased (8.5 ± 1.9%, p = 0.02) with a scattered pattern in luminal and deep neointima. Likewise, human in-stent restenosis atherectomy specimens (time after stent implantation 2–12 months) revealed a comparable extent of cellular rapamycin receptor expression (9.3 ± 1.0%) that significantly differed from that found in primary stable atheroma (1.3 ± 0.4%, p < 0.001). In conclusion, the rapamycin receptor is predominantly present during early neointima formation, while mature neointimal atheromas show a relatively low expression without confinement to luminal areas. Co-expression of FKBP12 and dendritic cell markers suggests that dendritic cells may be another important target for early and long-term rapamycin effects.
Perinatal Nutritional Iron Deficiency Impairs Hippocampus-Dependent Trace Eyeblink Conditioning in Rats
Authors: McEchron Matthew D. , Alexander Danielle N. , Gilmartin Marieke R. , Paronish Michael D.
Published: October 2007

Studies show that iron deficient (ID) children are at risk for poor cognitive development. Research also shows that ID may impair the development of the skeletal motor abilities. The present study sought to determine if perinatal ID in rats impairs a motor learning task called eyeblink conditioning. This task used a hippocampus-dependent trace version or non-hippocampus-dependent delay version. Rats were placed on ID or control diets from gestational day (G) 12 to postnatal day (P) 12. Young rats (P32–29) subjected to perinatal ID showed severe impairments in trace eyeblink conditioning but only minor impairments in delay eyeblink conditioning. A young moderate ID group (ID from G12 to P2) was also impaired in trace eyeblink conditioning. The ID rats that became adults (P64–69) showed only minor impairments in trace eyeblink conditioning. Young ID rats showed no deficits in motoric ability on a separate rotorod learning test. This study suggests that perinatal ID impairs motoric learning by altering higher-order learning centers like the hippocampus more so than by altering the skeletal motor system.
Fuelling America's Climatic Apocalypse
Authors: Leduc Timothy
Published: October 2007

This paper examines the powerful intersection of Christian fundamentalism and fossil fuel interests in the United States' Republican administration's policy response to climate change. Of particular interest is the increasing recognition that apocalyptic Christian beliefs are informing America's political economic and public understanding of environmental issues, thus allowing climate change to be interpreted from a religious frame of reference that could impact a viable response in a country whose GHG emissions are amongst the highest in the world. While liberal secularists may think the Christian apocalypse to be a misguided belief, scientific discourses on the potential interacting impacts of climatic changes and energy shortages offer an almost complementary rational depiction of apocalypse. By bringing these Christian and secular revelations into dialogue, the following interdisciplinary analysis offers a unique perspective on the way in which apocalyptic thought can both negatively and positively inform a political economic response to climate change.
Post-Secular Nature: Principles and Politics
Authors: Curry Patrick
Published: October 2007

Monist essentialism posits a worldview that has pervaded monotheistic religions and the imperatives of global capitalism. Relational pluralism acknowledges multiple perspectives and lends itself to a more ecocentric form of discourse. Monist essentialism has been associated with both religious and secular hegemony. Relational pluralism, while not advocating rootless relativism, allows for the importance of spirituality and the sacrality of nature for nature's sake. Hence, it may be deemed post-religious and post-secular. Wonder plays an important role in the adoption of a post-secular, spiritual worldview, and provides a welcome antidote to the crypto-religions of contemporary consumerism and the "god of progress." The ecocentric view must be distinguished from a facile veneration of nature, which can revert to insidious forms of anthropocentric monism or purely personal spirituality. Archaic religious paths as well as emerging disciplines such as ecological phenomenology can help lead to a re-enchantment of nature.
Women and the Sacred Earth: Hindu and Christian Ecofeminist Perspectives
Authors:   Dwivedi, Reid Lucy
Published: October 2007

Women's voices within the Christian and Hindu traditions contain theoretical and practical resources for dealing with issues of ecological concern. Hinduism's teachings about Mother Earth and newly crafted eco-feminist theories in Christianity provide a philosophical context for regarding the earth as sacred. The Chipko movement, organized and implemented by local women, prevented the commercial harvesting of lumber and its consequent habitat destruction in India's Uttaranchal Province. In North America, members of Christian women's religious orders have converted many of their properties to organic gardening and teaching centers, and into wildlife sanctuaries. Both movements are providing models for ecological sustainability.
Love Poetry by Arab Women A Survey
Authors: Borg Gert
Published: October 2007

Poetry by Arab women has often been neglected to a point, that many thought of it as hardly playing any role at all in the Arabic literary heritage, an exception being pre-Islamic marātī. This contribution tries to assess the importance of medieval love poetry by women in relation to Bauers far reaching conclusions about male love poetry in his Liebe und Liebesdichtung, etc. and its outline of Arab medieval "Mentalitätsgeschichte".The contribution that female love poetry offers to understand medieval Arab society is disappointing for two reasons:1. It is very much inspired by the everyday, almost banal vicissitudes that come with love;2. It hardly contains any wasf of the beloved, the means by which the poet(ess) might have been able to construct the necessary perspective to understand the emotional implications of love and passion and the intellectual reflection on it.
Advancing the New Public Diplomacy: A Public Relations Perspective
Authors: Fitzpatrick Kathy
Published: October 2007

As public diplomacy assumes a more prominent role in the diplomatic affairs of nations, scholars and practitioners are challenged to define the 'new' public diplomacy's purpose and goals, to develop the theoretical foundations of the discipline, and to articulate principles of practice for effectively and ethically achieving a nation's foreign affairs' objectives. This article demonstrates the potential for the public relations theory of relationship management to advance contemporary thought and practice in public diplomacy. The study finds that by defining public diplomacy's central purpose as relationship management, unifying the functions under one overarching concept, adopting a management (rather than communication) mindset, and recognizing the importance of diplomatic deeds that support communication practices, practitioners will be better equipped to conduct public diplomacy effectively.
Arguing Public Diplomacy: The Role of Argument Formations in US Foreign Policy Rhetoric
Authors: Hayden Craig
Published: October 2007

Since 2002, US communication-based foreign policies have resulted in the launch of two high-profile international broadcasting stations — Radio Sawa and al-Hurra television — as well as other failed ventures such as the 'Shared Values' documentary campaign and the Hi Arabic youth magazine. These policies have, at best, delivered mixed results as a form of public diplomacy for the United States. The principal objective of this article is to illuminate how governing beliefs about public diplomacy might have mitigated its success, by identifying the implicit policy imagination revealed in policy arguments. This article investigates the discursive imagination behind US international broadcasting programmes and how public debate outlines an 'argument formation' for US foreign-policy rhetoric. Three episodes of policy argument between 2001 and 2005 are assessed as demonstrative of a rhetorically constructed policy imagination that prompted a broadcasting strategy that was incompatible with the communicative norms of its targeted foreign audience.
Building Chains and Directing Flows
Authors: Zietsma Charlene , Winn Monika I.
Published: October 2007

This article aims to deepen the understanding of the processes and specific actions aimed at influencing and shaping business practices through dynamic stakeholder relationships. An inductive, longitudinal study of all players involved in a stakeholder conflict identified four clusters of influence tactics that were used by both secondary stakeholders and their target firms: issue raising, issue suppressing, positioning, and solution seeking. The stakeholders studied built elaborate influence chains and worked to direct influence flows. The study contributes to stakeholder theory by offering a refined understanding of both bilateral and mutual-influence tactics, expanding the theory's focus beyond bilateral relationships, and highlighting the use of dependence relationships among multiple embedded organizations to build influence over a specific target, and more generally, an organizational field. These findings are discussed in light of work on social movement organizations and institutional theory.
Employee Alienation in the Quick Service Restaurant Industry
Authors: DiPietro Robin B. , Pizam Abraham
Published: October 2007

An exploratory study conducted among 595 U.S. quick service restaurant hourly employees and managers for the purpose of measuring their level of work alienation finds that a significant proportion of the respondents expressed feelings of work alienation. The feelings seemed to be more prevalent among hourly employees, males, those younger, those more educated, and African Americans. But most important, the study indicates that employees' alienation was unequally distributed among the restaurants within the sample, therefore possibly suggesting that work alienation is not necessarily caused by the technology employed and/or the nature of the jobs but rather by the managerial styles and practices in each restaurant.
The Antecedents and Consequences of Psychological Empowerment: The Case of Taiwan's Hotel Companies
Authors: Chiang Chun-Fang , Jang SooCheong (Shawn)
Published: October 2007

Empowering employees to meet customers' needs or solve their problems can be one of the best ways to satisfy customers. The objectives of this study are to investigate the extent to which the level of psychological empowerment (meaning, competence, self-determination, and impact) is perceived by employees; to examine whether leadership, trust, and organizational culture function as the antecedents of empowerment; and to look into whether empowerment influences job satisfaction and organizational commitment. Using structural equation modeling, this study supports the conclusion that leadership has a positive, direct effect on trust and organizational culture, which are important antecedents related positively to psychological empowerment constructs. The study also suggests that self-determination in psychological empowerment has a significant effect on job satisfaction and is related to organizational commitment.
The tertiary structure and domain organization of coagulation factor VIII
Authors: Shen Betty W. , Spiegel Paul Clint , Chang Chong-Hwan , Huh Jae-Wook , Lee Jung-Sik , Kim Jeanman , Kim Young-Ho , Stoddard Barry L.
Published: October 2007

Factor VIII (fVIII) is a serum protein in the coagulation cascade that nucleates the assembly of a membrane-bound protease complex on the surface of activated platelets at the site of a vascular injury. Hemophilia A is caused by a variety of mutations in the factor VIII gene and typically requires replacement therapy with purified protein. We have determined the structure of a fully active, recombinant form of factor VIII (r-fVIII), which consists of a heterodimer of peptides, respectively containing the A1-A2 and A3-C1-C2 domains. The structure permits unambiguous modeling of the relative orientations of the 5 domains of r-fVIII. Comparison of the structures of fVIII, fV, and ceruloplasmin indicates that the location of bound metal ions and of glycosylation, both of which are critical for domain stabilization and association, overlap at some positions but have diverged at others.
The pheromone-induced nuclear accumulation of the Fus3 MAPK in yeast depends on its phosphorylation state and on Dig1 and Dig2
Authors: Blackwell Ernest , Kim Hye-Jin N , Stone David E
Published: October 2007

Background

Like mammalian MAP kinases, the mating-specific Fus3 MAPK of yeast accumulates in the nuclei of stimulated cells. Because Fus3 does not appear to be subjected to active nucleo-cytoplasmic transport, it is not clear how its activation by mating pheromone effects the observed change in its localization. One possibility is that the activation of Fus3 changes its affinity for nuclear and cytoplasmic tethers.

Results

Dig1, Dig2, and Ste12 are nuclear proteins that interact with Fus3. We found that the pheromone-induced nuclear accumulation of a Fus3-GFP reporter is reduced in cells lacking Dig1 or Dig2, whereas Fus3T180AY182A-GFP localization was unaffected by the absence of these proteins. This suggests that Dig1 and Dig2 contribute to the retention of phosphorylated Fus3 in the nucleus. Moreover, overexpression of Ste12 caused the hyper-accumulation of Fus3-GFP (but not Fus3T180AY182A-GFP) in the nuclei of pheromone-treated cells, suggesting that Ste12 also plays a role in the nuclear retention of phosphorylated Fus3, either by directly interacting with it or by transcribing genes whose protein products are Fus3 tethers. We have previously reported that overexpression of the Msg5 phosphatase inhibits the nuclear localization of Fus3. Here we show that this effect depends on the phosphatase activity of Msg5, and provide evidence that both nuclear and cytoplasmic Msg5 can affect the localization of Fus3.

Conclusion

Our data are consistent with a model in which the pheromone-induced phosphorylation of Fus3 increases its affinity for nuclear tethers, which contributes to its nuclear accumulation and is antagonized by Msg5.
Missense mutations in Desmocollin-2 N-terminus, associated with arrhythmogenic right ventricular cardiomyopathy, affect intracellular localization of desmocollin-2 in vitro
Authors: Beffagna Giorgia , De Bortoli Marzia , Nava Andrea , Salamon Michela , Lorenzon Alessandra , Zaccolo Manuela , Mancuso Luisa , Sigalotti Luca , Bauce Barbara , Occhi Gianluca , Basso Cristina , Lanfranchi Gerolamo , Towbin Jeffrey A , Thiene Gaetano , Danieli Gian Antonio , Rampazzo Alessandra
Published: October 2007

Background

Mutations in genes encoding desmosomal proteins have been reported to cause arrhythmogenic right ventricular cardiomyopathy (ARVC), an autosomal dominant disease characterised by progressive myocardial atrophy with fibro-fatty replacement.

We screened 54 ARVC probands for mutations in desmocollin-2 (DSC2), the only desmocollin isoform expressed in cardiac tissue.

Methods

Mutation screening was performed by denaturing high-performance liquid chromatography and direct sequencing.

To evaluate the pathogenic potentials of the DSC2 mutations detected in patients affected with ARVC, full-length wild-type and mutated cDNAs were cloned in eukaryotic expression vectors to obtain a fusion protein with green fluorescence protein (GFP); constructs were transfected in neonatal rat cardiomyocytes and in HL-1 cells.

Results

We identified two heterozygous mutations (c.304G>A (p.E102K) and c.1034T>C (p.I345T)) in two probands and in four family members. The two mutations p.E102K and p.I345T map to the N-terminal region, relevant to adhesive interactions.

In vitro functional studies demonstrated that, unlike wild-type DSC2, the two N-terminal mutants are predominantly localised in the cytoplasm.

Conclusion

The two missense mutations in the N-terminal domain affect the normal localisation of DSC2, thus suggesting the potential pathogenic effect of the reported mutations. Identification of additional DSC2 mutations associated with ARVC may result in increased diagnostic accuracy with implications for genetic counseling.
Field assessment of a model tuberculosis outbreak response plan for low-incidence areas
Authors: Freimanis Hance Laura , Steingart Karen R , Hahn Christine G , Pascopella Lisa , Nolan Charles M
Published: October 2007

Background

For a regional project in four low-incidence states, we designed a customizable tuberculosis outbreak response plan. Prior to dissemination of the plan, a tuberculosis outbreak occurred, presenting an opportunity to perform a field assessment of the plan. The purpose of the assessment was to ensure that the plan included essential elements to help public health professionals recognize and respond to outbreaks.

Methods

We designed a semi-structured questionnaire and interviewed all key stakeholders involved in the response. We used common themes to assess validity of and identify gaps in the plan. A subset of participants provided structured feedback on the plan.

Results

We interviewed 11 public health and six community stakeholders. The assessment demonstrated that (1) almost all of the main response activities were reflected in the plan; (2) the plan added value by providing a definition of a tuberculosis outbreak and guidelines for communication and evaluation. These were areas that lacked written protocols during the actual outbreak response; and (3) basic education about tuberculosis and the interpretation and use of genotyping data were important needs. Stakeholders also suggested adding to the plan questions for evaluation and a section for specific steps to take when an outbreak is suspected.

Conclusion

An interactive field assessment of a programmatic tool revealed the value of a systematic outbreak response plan with a standard definition of a tuberculosis outbreak, guidelines for communication and evaluation, and response steps. The assessment highlighted the importance of education and training for tuberculosis in low-incidence areas.
Diagnostic utility of p501s (prostein) in comparison to prostate specific antigen (PSA) for the detection of metastatic prostatic adenocarcinoma
Authors: Yin Ming , Dhir Rajiv , Parwani Anil V
Published: October 2007

Background

Immunohistochemical detection of prostate specific antigen (PSA) is widely used to identify metastatic prostatic adenocarcinoma. However, PSA may not be expressed in some poorly differentiated prostatic carcinomas and its immunoreactivity has been found in some non-prostatic tissues. P501s (prostein) is a prostate-specific marker that is expressed in the cytoplasm of benign and malignant prostatic glandular cells. It has not been detected in any other normal or malignant tissues. The purpose of this study was to evaluate the expression of P501s in metastatic prostatic adenocarcinoma and compare its expression with PSA.

Methods

Immunohistochemical stains with anti-P501s antibodies were performed on 5-micron sections of tissue microarray (TMA) specimens. The TMA is constructed with normal donor prostates (NDP), prostatic adenocarcinoma (PRCA), non-neoplastic prostatic tissues adjacent to malignant glands (NAT), benign prostatic hyperplasia (BPH), high-grade prostatic neoplasia (PIN), metastatic adenocarcinoma to lymph nodes (MLN), metastatic adenocarcinoma to other sites (MC), and samples of benign testis, colon, adrenal and kidney. The two groups of metastatic lesions were also subjected to stains with antibodies to PSA. A composite score (ranging from 0 to 3) was assigned to score intensity of staining.

Results

Granular staining pattern of p501s was seen in all benign glands (score = 1.77 – 2.1) and malignant acini (score = 1.52) at the apical aspect of cytoplasm, predominantly adjacent to the nuclei. No staining was observed in controls including testis, colon, adrenal and kidney. The MLN group received a score of 1.0, with 10% of cases negative for p501s. The MC cases had a score of 0.64, with 16.7% of case showing loss of p501s expression. Although the metastatic lesions demonstrated similar rate of negative expression with PSA antibody, only 2 MC cases (3.3%) showed simultaneous negative stains for both P501S and PSA.

Conclusion

P501s is an organ specific marker for benign and malignant prostatic epithelial cells. Its characteristic cytoplasmic stain pattern provides an additional valuable immunomarker for detection of metastatic prostatic malignancy, even though the intensity of its expression is reduced, as in the case with PSA. Simultaneous stains with P501S and PSA will greatly improve the detection rate and identify a significant majority of the metastases.
Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues
Authors: Shahrara Shiva , Castro-Rueda Hernan P , Haines G Kenneth , Koch Alisa E
Published: October 2007

The focal adhesion kinase (FAK) family kinases, including FAK and proline-rich kinase 2 (Pyk)2, are the predominant mediators of integrin αvβ3 signaling events that play an important role in cell adhesion, osteoclast pathology, and angiogenesis, all processes important in rheumatoid arthritis (RA). Using immunohistochemical and western blot analysis, we studied the distribution of phospho (p)FAK, pPyk2, pSrc, pPaxillin and pPLCγ in the synovial tissue (ST) from patients with RA, osteoarthritis (OA) and normal donors (NDs) as well as in RA ST fibroblasts and peripheral blood differentiated macrophages (PB MΦs) treated with tumor necrosis factor-α (TNFα) or interleukin-1β (IL1β). RA and OA STs showed a greater percentage of pFAK on lining cells and MΦs compared with ND ST. RA ST fibroblasts expressed pFAK at baseline, which increased with TNFα or IL1β stimulation. Pyk2 and Src were phosphorylated more on RA versus OA and ND lining cells and MΦs. pPyk2 was expressed on RA ST fibrobasts but not in MΦs at baseline, however it was upregulated upon TNFα or IL1β activation in both cell types. pSrc was expressed in RA ST fibroblasts and MΦs at baseline and was further increased by TNFα or IL1β stimulation. pPaxillin and pPLCγ were upregulated in RA versus OA and ND lining cells and sublining MΦs. Activation of the FAK family signaling cascade on RA and OA lining cells may be responsible for cell adhesion and migration into the diseased STs. Therapies targeting this novel signaling pathway may be beneficial in RA.
Quantification of antiretroviral drugs for HIV-1 in the male genital tract: current data, limitations and implications for laboratory analysis
Authors: Chan Derek J , Ray John E
Published: October 2007

Antiretroviral therapy has reduced the morbidity and mortality associated with HIV-1/AIDS in developed countries. Viral replication in blood plasma is suppressed by antiretroviral drugs, whereas virus in the male genital tract is genetically and phenotypically unique and may not be suppressed. This viral compartmentalization affects antiretroviral drug penetration of the male genital tract and capacity for antiretroviral therapy to reduce sexual transmission. The problem of having two distinct viral populations within any given individual is compounded by the fact that antiretroviral drugs penetrate semen to varying degrees. Incomplete suppression of genital tract virus may yield drug-resistant virus and increase the risk of sexual transmission. This review critically appraises current studies of antiretroviral drug quantification in semen and suggests recommendations to address observed limitations.
Urea inclusion compounds of enalapril maleate for the improvement of pharmaceutical characteristics
Authors: Thakral Seema , Madan A K
Published: October 2007

Urea is a well known adductor for linear organic compounds. In the present study, enalapril maleate, a substituted cyclic organic compound, was successfully included in urea together with a suitable rapidly adductible endocyte (RAE). Formation of the urea inclusion compound was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction. The modified Zimmerschied calorimetric method was used to estimate the minimum amount of RAE required for adduction of enalapril maleate in urea. Urea-enalapril maleate-RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behaviour studied by differential scanning calorimetry. Regression analysis revealed an excellent r2 value with regard to the influence of the relative proportion of RAE on the heat of decomposition. The inclusion compounds were found to exhibit good content uniformity and improved dissolution profile as demonstrated by increased dissolution efficiency. Studies revealed that urea inclusion may be a promising alternative for the formulation of potent poorly soluble drugs into immediate release products.
Effect of absorption rate on pharmacokinetics of ibuprofen in relation to chiral inversion in humans
Authors: Ding Guohua , Liu Yang , Sun Jiewen , Takeuchi Yuriko , Toda Takaki , Hayakawa Toru , Fukushima Shoji , Kishimoto Shuichi , Lin Wenhui , Inotsume Nobuo
Published: October 2007

The effect of absorption rate on the pharmacokinetics of ibuprofen enantiomers was investigated in 12 healthy Han Chinese male volunteers following oral administration of immediate-release (IR) and sustained-release (SR) preparations containing racemic ibuprofen (rac-ibuprofen). The area under the curve of the plasma concentration-time curve (AUC; (mean ± s.d.) values for rac-ibuprofen were 192.90 ± 43.47 for the SR preparation and 195.90 ± 31.69 μg h mL−1 for the IR preparation. AUC values for the enantiomers after administration of the SR formulation were 55.38 ± 17.79 and 92.51 ± 30.68 μg h mL−1 for R- and S-ibuprofen, respectively, and were 65.94 ± 20.06 and 100.81 ± 32.28 μg h mL−1 for R- and S-ibuprofen after administration of the IR preparation. These values did not differ significantly. Cmax values were significantly decreased with the SR preparation: 25.11 ± 5.71, 12.24 ± 3.79 and 12.38 ± 3.55 μg mL−1 for rac-, R-, and S-ibuprofen, respectively, after administration of the SR preparation, vs 46.21 ± 8.20, 20.82 ± 5.90 and 23.46 ± 7.30 μg mL−1 for rac-, R-, and S-ibuprofen, respectively, after administration of the IR preparation. Mean residence time was significantly increased: 7.01 ± 1.29, 5.52 ± 1.25 and 7.04 ± 1.30 h for rac-, R-, and S-ibuprofen, respectively, after administration of the SR preparation vs 4.34 ± 0.89, 3.43 ± 0.64 and 4.51 ± 0.79 h for rac-, R-, and S-ibuprofen, respectively, after administration of the IR preparation. AUC values for S-ibuprofen were significantly larger than those for R-ibuprofen in both preparations, indicating unidirectional chiral inversion. The S/R ratio of serum concentrations of enantiomers was 1.78-fold higher at 6 h after administration of the SR preparation compared with the IR preparation (P < 0.01).

These results indicate that ibuprofen undergoes pre-systemic chiral inversion in parallel with a systemic process and that the clinical effects of rac-ibuprofen in humans depend on the absorption rate.
Inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells
Authors: Shim Chang-Koo , Cheon Eun-Pa , Kang Keon Wook , Seo Ki-Soo , Han Hyo-Kyung
Published: October 2007

This study aimed to investigate the inhibition effect of flavonoids on monocarboxylate transporter 1 (MCT1) in Caco-2 cells. The cellular uptake of benzoic acid was examined in the presence and the absence of naringin, naringenin, morin, silybin and quercetin in Caco-2 cells. All the tested flavonoids except naringin significantly inhibited (P < 0.05) the cellular uptake of [14C]-benzoic acid. Particularly, naringenin and silybin exhibited strong inhibition effects with IC50 values of 23.4 and 30.2 μm, respectively. Kinetic analysis indicated that the inhibition mode of naringenin and silybin on MCT1 activity was competitive with a Ki of 15∼20 μm. The effect of flavonoids on the gene expression of MCT1 was also examined by using RT-PCR and western blot analysis. Results indicated that the expression level of MCT1 was not affected by the treatment with naringenin or silybin. The cellular accumulation of naringenin in Caco-2 cells was not changed in the presence of benzoic acid or l-lactic acid, implying that naringenin might not be a substrate of MCT1. In conclusion, some flavonoids appeared to be competitive inhibitors of MCT1, suggesting the potential for diet-drug interactions between flavonoids and MCT1 substrates.
Effects of quinine on the intracellular calcium level and membrane potential of PC 12 cultures
Authors: Akiyoshi Takeshi , Tanaka Naoko , Nakamura Tomoko , Matzno Sumio , Shinozuka Kazumasa , Uchida Takahiro
Published: October 2007

The mechanism for the perception of bitterness appears to be quite complicated, even for quinine, which is a model bitter substance, and thus has yet to be completely elucidated. To investigate the possibility of being able to predict the bitterness of quinine solutions, we examined the effects of quinine on intracellular calcium ion concentration ([Ca2+]i) and membrane potentials in PC 12 cultures. [Ca2+]i and membrane potentials were analysed by fluorescence confocal microscopic imaging using the Ca2+-sensitive probe Calcium Green 1/AM and the membrane potential-sensitive probe bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC4(3)). Quinine elicited an increase in the membrane potential along with a concentration-dependent increase in [Ca2+]i. These increases were inhibited by extracellular Ca2+-free conditions, thapsigargin, which is a Ca2+-pump inhibitor, and U73122, which is a phospholipase C inhibitor. The quinine-induced increase in [Ca2+]i levels was inhibited by nifedipine, an L-type Ca2+-channel blocker, ω-conotoxin, a T-type Ca2+-channel blocker, and BMI-40, which is a bitterness-masking substance. These results suggest that responses in PC 12 cultures may be used as a simple model of bitterness perception.
The gastric emptying of food as measured by gamma-scintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions
Authors: Podczeck Fridrun , Mitchell Catherine L , Newton J Michael , Evans David , Short Michael B
Published: October 2007

A study in human volunteers has been designed to evaluate the influence of different food regimes on the gastric emptying of 3 mm and 10 mm diameter tablets. Dextrose and beef drinks were used as liquid food; a mixture of minced beef and mashed potato (shepherd's pie) was used as a solid meal. The gastric emptying of these foods was monitored simultaneously with electrical impedance tomography (EIT) and gamma-scintigraphy (GS), and was quantified in terms of the time before gastric emptying started, the lag time, the mean gastric residence time (MGRT) and its variance (VGRT), and the time for complete emptying. The gastric emptying time of the tablets was established by monitoring the position of the tablets, which had been labelled with suitable radio isotopes, by GS. The two systems for monitoring gastric emptying of the foods did not provide equivalent results: times obtained with EIT were generally shorter than those obtained with GS for the liquid foods, but were longer for the solid meal. There was only a slight difference in the emptying times of the two liquid foods, whereas values for MGRT, VGRT and the time for complete emptying were considerably longer for the solid meal. In nearly all instances the tablets emptied after the foods had emptied completely from the stomach. Gastric emptying times were longer for the 3 mm tablets than the 10 mm tablets, whatever food they were taken with. The difference between the median emptying times was significant when the meal was either a dextrose solution or a beef drink, but not when the meal was shepherd's pie. The increase in gastric emptying time of tablets induced by solid food was greater than that associated with the differences in tablet size. By providing a protocol that did not allow the administration of further food until after the tablets had emptied from the stomach, no tablet emptying times exceeded 6 h.
Effect of 2-hydroxy 4-methoxy benzoic acid on an experimental model of hyperlipidaemia, induced by chronic ethanol treatment
Authors: Saravanan Nadana , Nalini Namasivayam
Published: October 2007

The aim of the present study was to determine the effect of 2-hydroxy 4-methoxy benzoic acid (HMBA), the active principle of Hemidesmus indicus, an indigenous Ayurvedic medicinal plant in India. We investigated the effect of HMBA on hyperlipidaemia induced by ethanol, exploring food intake, body weight, and hepatic and plasma lipids and lipoproteins. Male Wistar rats weighing 130–180 g were given ethanol (5 g kg−1 p.o.) daily for 30 days. Subsequently, ethanol-fed rats were given HMBA intragastrically at a dose of 200 μg kg−1 per day for 30 days. At the end of the total experimental period of 60 days, plasma concentrations of total cholesterol (CHO), triglycerides (TG), lipoproteins (LP), phospholipids (PL), free fatty acids (FFA) and lipoprotein lipase (LPL), and hepatic CHO, TG and PL were measured. Treatment of ethanol-fed rats with HMBA significantly decreased plasma CHO, TG, LP, PL and FFA and hepatic CHO, TG and PL, and increased plasma LPL concentrations compared with values in untreated ethanol-fed rats (all P < 0.05). Food intake and average body weight at the end of the experimental period were significantly increased by HMBA administration. In conclusion, administration of HMBA decreased lipids and lipoprotein concentrations significantly in an animal model of ethanol-induced hyperlipidaemia.