bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficit of complex I activity in human skin fibroblasts with chromosome 21 trisomy and overproduction of reactive oxygen species by mitochondria: involvement of the cAMP/PKA signalling pathway
Authors: Valenti Daniela , Manente Gabriella Arcangela , Moro Laura , Marra Ersilia , Vacca Rosa Anna 
Published: March 2011

DS (Down's syndrome) is the most common human aneuploidy associated with mental retardation and early neurodegeneration. Mitochondrial dysfunction has emerged as a crucial factor in the pathogenesis of numerous neurological disorders including DS, but the cause of mitochondrial damage remains elusive. In the present study, we identified new molecular events involved in mitochondrial dysfunction which could play a role in DS pathogenesis. We analysed mitochondrial respiratory chain function in DS-HSFs (Down's syndrome human foetal skin fibroblasts; human foetal skin fibroblasts with chromosome 21 trisomy) and found a selective deficit in the catalytic efficiency of mitochondrial complex I. The complex I deficit was associated with a decrease in cAMP-dependent phosphorylation of the 18 kDa subunit of the complex, due to a decrease in PKA (protein kinase A) activity related to reduced basal levels of cAMP. Consistently, exposure of DS-HSFs to db-cAMP (dibutyryl-cAMP), a membrane-permeable cAMP analogue, stimulated PKA activity and consequently rescued the deficit of both the cAMP-dependent phosphorylation and the catalytic activity of complex I; conversely H89, a specific PKA inhibitor, suppressed these cAMP-dependent activations. Furthermore, in the present paper we report a 3-fold increase in cellular levels of ROS (reactive oxygen species), in particular superoxide anion, mainly produced by DS-HSF mitochondria. ROS accumulation was prevented by db-cAMP-dependent activation of complex I, suggesting its involvement in ROS production. Taken together, the results of the present study suggest that the drastic decrease in basal cAMP levels observed in DS-HSFs participates in the complex I deficit and overproduction of ROS by DS-HSF mitochondria.
Novel mechanism of inhibition of human angiotensin-I-converting enzyme (ACE) by a highly specific phosphinic tripeptide
Authors: Akif Mohd , Schwager Sylva L. , Anthony Colin S. , Czarny Bertrand , Beau Fabrice , Dive Vincent , Sturrock Edward D. , Acharya K. Ravi 
Published: March 2011

Human ACE (angiotensin-I-converting enzyme) has long been regarded as an excellent target for the treatment of hypertension and related cardiovascular diseases. Highly potent inhibitors have been developed and are extensively used in the clinic. To develop inhibitors with higher therapeutic efficacy and reduced side effects, recent efforts have been directed towards the discovery of compounds able to simultaneously block more than one zinc metallopeptidase (apart from ACE) involved in blood pressure regulation in humans, such as neprilysin and ECE-1 (endothelin-converting enzyme-1). In the present paper, we show the first structures of testis ACE [C-ACE, which is identical with the C-domain of somatic ACE and the dominant domain responsible for blood pressure regulation, at 1.97Å (1 Å=0.1 nm)] and the N-domain of somatic ACE (N-ACE, at 2.15Å) in complex with a highly potent and selective dual ACE/ECE-1 inhibitor. The structural determinants revealed unique features of the binding of two molecules of the dual inhibitor in the active site of C-ACE. In both structures, the first molecule is positioned in the obligatory binding site and has a bulky bicyclic P1′ residue with the unusual R configuration which, surprisingly, is accommodated by the large S2′ pocket. In the C-ACE complex, the isoxazole phenyl group of the second molecule makes strong pi–pi stacking interactions with the amino benzoyl group of the first molecule locking them in a ‘hand-shake’ conformation. These features, for the first time, highlight the unusual architecture and flexibility of the active site of C-ACE, which could be further utilized for structure-based design of new C-ACE or vasopeptidase inhibitors.
Next-generation Akt inhibitors provide greater specificity: effects on glucose metabolism in adipocytes
Authors: Tan Shixiong , Ng Yvonne , James David E. 
Published: March 2011

Many human tumours exhibit activation of the PI3K (phosphoinositide 3-kinase)/Akt pathway, and inhibition of this pathway slows tumour growth. This led to the development of specific Akt inhibitors for in vivo use. However, activation of Akt is also necessary for processes including glucose metabolism. Therefore a potential complication of such anticancer drugs is insulin resistance and/or diabetes. In the process of characterizing the metabolic effects of early-phase Akt inhibitors, we discovered an off-target inhibitory effect on mammalian facilitative glucose transporters. In view of the crucial role of glucose transport for all mammalian cells, such an off-target effect would have major implications for further development of this family of compounds. In the present study, we have characterized a next-generation Akt inhibitor, MK-2206. MK-2206 is an orally active allosteric Akt inhibitor under development for treating solid tumours. We report that MK-2206 potently inhibits Thr308Akt and Ser473Akt phosphorylation in 3T3-L1 adipocytes (IC50 0.11 and 0.18 μM respectively) as well as downstream effects of insulin on GLUT4 (glucose transporter 4) translocation (IC50 0.47 μM) and glucose transport (IC50 0.14 μM). Notably, the potency of MK-2206 is approximately 1 log higher than previous inhibitors and its specificity is significantly improved with modest inhibitory effects on glucose transport in GLUT4-expressing adipocytes and GLUT1-rich human erythrocytes, independently of Akt. Nevertheless, MK-2206 clearly has potent effects on Akt2, the principal isoform involved in peripheral insulin action, in which case insulin resistance will probably be a major complication following in vivo administration. We conclude that MK-2206 provides an optimal tool for studying the effects of Akt in vitro.
Impaired flow-mediated dilatation response in uncomplicated Type 1 diabetes mellitus: influence of shear stress and microvascular reactivity
Authors: Lockhart Christopher J. , Agnew Christina E. , McCann Aaron , Hamilton Paul K. , Quinn Cathy E. , McCall Damien O. , Plumb Rick D. , McClenaghan Vivienne C. N. , McGivern R. Canice , Harbinson Mark T. , McVeigh Gary E. 
Published: March 2011

Impaired FMD (flow-mediated dilatation) has traditionally been recognized as an indirect marker of NO bioactivity, occurring in disease states such as DM (diabetes mellitus). Endothelium-dependent FMD is a homoeostatic response to short-term increases in local shear stress. Microvascular dysfunction in DM influences blood flow velocity patterns. We explored the determinants of the FMD response in relation to evoked DSS (diastolic shear stress) and forearm microcirculation haemodynamics by quantifying changes in Doppler flow velocity waveforms between groups. Forty patients with uncomplicated Type 1 DM and 32 controls underwent B-mode and Doppler ultrasound scanning to interrogate the brachial artery. Postischaemic Doppler velocity spectral envelopes were recorded and a wavelet-based time-frequency spectral analysis method was employed to track change in distal microcirculatory haemodynamics. No difference in baseline brachial artery diameter was evident between the groups (4.15 compared with 3.94 mm, P=0.23). FMD was significantly impaired in patients with Type 1 DM (3.95 compared with 7.75%, P&lt;0.001). Endothelium-independent dilatation in response to GTN (glyceryl trinitrate) was also significantly impaired (12.07 compared with 18.77%, P&lt;0.001). DSS (dyn/cm2) was significantly reduced in the patient group (mean 20.19 compared with 29.5, P=0.001). Wavelet interrogation of postischaemic flow velocity waveforms identified significant differences between groups. In conclusion, DSS, microcirculatory function and endothelium-independent vasodilatation in response to GTN are important determinants that impact on the magnitude of FMD response and are impaired in patients with Type 1 DM. Impaired FMD response is multifactorial in origin and cannot be attributed solely to a diminished NO bioavailability.
Organelles Contribute Differentially to Reactive Oxygen Species-Related Events during Extended Darkness
Authors: Rosenwasser Shilo , Rot Ilona , Sollner Evelyn , Meyer Andreas J. , Smith Yoav , Leviatan Noam , Fluhr Robert , Friedman Haya 
Published: March 2011

Abstract
Treatment of Arabidopsis (Arabidopsis thaliana) leaves by extended darkness generates a genetically activated senescence program that culminates in cell death. The transcriptome of leaves subjected to extended darkness was found to contain a variety of reactive oxygen species (ROS)-specific signatures. The levels of transcripts constituting the transcriptome footprints of chloroplasts and cytoplasm ROS stresses decreased in leaves, as early as the second day of darkness. In contrast, an increase was detected in transcripts associated with mitochondrial and peroxisomal ROS stresses. The sequential changes in the redox state of the organelles during darkness were examined by redox-sensitive green fluorescent protein probes (roGFP) that were targeted to specific organelles. In plastids, roGFP showed a decreased level of oxidation as early as the first day of darkness, followed by a gradual increase to starting levels. However, in mitochondria, the level of oxidation of roGFP rapidly increased as early as the first day of darkness, followed by an increase in the peroxisomal level of oxidation of roGFP on the second day. No changes in the probe oxidation were observed in the cytoplasm until the third day. The increase in mitochondrial roGFP degree of oxidation was abolished by sucrose treatment, implying that oxidation is caused by energy deprivation. The dynamic redox state visualized by roGFP probes and the analysis of microarray results are consistent with a scenario in which ROS stresses emanating from the mitochondria and peroxisomes occur early during darkness at a presymptomatic stage and jointly contribute to the senescence program.
Diagnosing pulmonary embolism: a comparison of clinical probability scores
Authors: Hogg Kerstin , Thomas Deborah , Mackway‐Jones Kevin , Lecky Fiona , Cruickshank Kennedy 
Published: March 2011

SummaryPulmonary embolism (PE) is a major cause of community and in‐hospital mortality. This study aimed to compare the performance of the British Thoracic Society (BTS) score to the Wells’ score in diagnosing PE. Data from two separate prospective diagnostic PE studies were analysed. All patients underwent gold standard investigation to determine the presence or absence of PE, together with a 3‐month follow‐up. The posttest prevalence of PE was compared using both scores and the receiver operating characteristic (ROC) curves. Seven hundred and seventy‐nine patients were consented and investigated for PE. In patients with pleuritic chest pain, respiratory rate <20 breaths/min and absence of dyspnoea, 4·0% [95% confidence interval (CI) 1·9–7·9%] had PE. The BTS score allocated 463/779 patients as low probability, compared to 565/779 according to the Wells’ score. Both scores identified a low risk group in the Manchester Investigation of Pulmonary Embolism Diagnosis cohort, however the BTS low probability group in the Thromboembolism Assessment and Diagnosis study had a prevalence of 9·7% (95% CI 5·8–15·9%). For the BTS score, the areas under the ROC curves were 0·67 (95% CI 0·61–0·72) and 0·71 (95% CI 0·61–0·75). For the Wells’ score these were 0·76 (95%CI 0·71–0·81) and 0·68 (95%CI 0·64–0·73). Given the lack of BTS validation studies to date, the Wells’ score appears to be the safer assessment option.
Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node‐positive breast cancers: a long‐term follow‐up study
Authors: Yoshioka Takako , Umekita Yoshihisa , Ohi Yasuyo , Souda Masakazu , Sagara Yoshiatsu , Sagara Yasuaki , Sagara Yoshiaki , Rai Yoshiaki , Tanimoto Akihide 
Published: March 2011

Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, Sagara Y, Rai Y & Tanimoto A (2011) Histopathology58, 608–616 Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node‐positive breast cancers: a long‐term follow‐up studyAims:  Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells. The aim was to determine the prognostic significance of ALDH1 expression in a long‐term follow‐up study.Methods and results:  Immunohistochemical analyses were performed on 257 invasive ductal carcinomas (IDCs), 109 matched lymph node metastases and 190 ductal carcinomas in situ (DCISs), using paraffin‐embedded sections. ALDH1 expression was found in 26% of IDCs, and correlated with larger tumour size (P = 0.007), high histological grade (P < 0.001), HER2 overexpression (P < 0.001) and negative hormone receptor status (P < 0.001). ALDH1 expression was observed in 14% of DCISs but was not correlated with any clinicopathological parameter. The IDC patients were followed up for 7–190 months (median: 120 months), and groups with ALDH1 expression had shorter relapse‐free survival (P = 0.0013) and overall survival (OS) (P = 0.0005) by log‐rank test. By Cox’s multivariate analysis, it had a weak effect on OS (P = 0.047), and its most significant effect on OS was observed in node‐positive groups (P = 0.013). No significant differences in OS stratified by ALDH1 expression status in lymph node metastases were noted.Conclusions:  ALDH1 expression in primary cancer is an independent prognostic factor in node‐positive breast cancer patients.
Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy, including detailed review of epithelial atypia
Authors: Rakha Emad A , Ho Bernard C , Naik Veena , Sen Soumadri , Hamilton Lisa J , Hodi Zsolt , Ellis Ian O , Lee Andrew H S 
Published: March 2011

Rakha E A, Ho B C, Naik V, Sen S, Hamilton L J, Hodi Z, Ellis I O & Lee A H S (2011) Histopathology 58, 626–632 Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy, including detailed review of epithelial atypiaAims:  To provide updated evidence of the outcome of breast lesions of uncertain malignant potential (B3) and suspicious of malignancy (B4) diagnosed on needle core biopsy (NCB) and analyse the outcome of the different types of intraductal epithelial atypia.Methods and results:  One‐hundred and forty‐nine B3 and 26 B4 NCBs diagnosed over a 2‐year period (2007–2008) were compared with those diagnosed over a previous 2‐year period (1998–2000). The proportion of B3 diagnoses increased from 3.1% to 4.5%, and the positive predictive value (PPV) of malignancy of a B3 core decreased from 25% to 10%. Increased diagnosis of radial scar and reductions in the PPV of lobular neoplasia and of atypical intraductal proliferation may explain the reduction in the PPV of the B3 group as a whole. There were no significant changes in the proportion of B4 diagnosis (1.1% and 0.8%) or the PPV of B4 (83% and 88%). Review of cores with intraductal atypia showed a wide range of PPVs, from 100% for suspicious of ductal carcinoma in situ, to 40% for atypical ductal hyperplasia categorized as B3, and 14% for isolated flat epithelial atypia.Conclusion:  The study has found a decrease in the PPV for a B3 diagnosis and suggests possible explanations.
The therapeutic efficacy of human adipose tissue‐derived mesenchymal stem cells on experimental autoimmune hearing loss in mice
Authors: Zhou Yixuan , Yuan Jingdong , Zhou Bin , Lee Austin J. , Lee Albert J. , Ghawji Jr Maher , Yoo Tai June 
Published: March 2011

SummaryAutoimmune inner ear disease is characterized by progressive, bilateral although asymmetric, sensorineural hearing loss. Patients with autoimmune inner ear disease had higher frequencies of interferon‐γ‐producing T cells than did control subjects tested. Human adipose‐derived mesenchymal stem cells (hASCs) were recently found to suppress effector T cells and inflammatory responses and therefore have beneficial effects in various autoimmune diseases. The aim of this study was to examine the immunosuppressive activity of hASCs on autoreactive T cells from the experimental autoimmune hearing loss (EAHL) murine model. Female BALB/c mice underwent β‐tubulin immunization to develop EAHL; mice with EAHL were given hASCs or PBS intraperitoneally once a week for 6 consecutive weeks. Auditory brainstem responses were examined over time. The T helper type 1 (Th1)/Th17‐mediated autoreactive responses were examined by determining the proliferative response and cytokine profile of splenocytes stimulated with β‐tubulin. The frequency of regulatory T (Treg) cells and their suppressive capacity on autoreactive T cells were also determined. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen‐specific Th1/Th17 cells and induced the production of anti‐inflammatory cytokine interleukin‐10 in splenocytes. They also induced the generation of antigen‐specific CD4+ CD25+ Foxp3+  Treg cells with the capacity to suppress autoantigen‐specific T‐cell responses. The experiment demonstrated that hASCs are one of the important regulators of immune tolerance with the capacity to suppress effector T cells and to induce the generation of antigen‐specific Treg cells.
Recent adverse trends in semen quality and testis cancer incidence among Finnish men
Authors: Jørgensen N. , Vierula M. , Jacobsen R. , Pukkala E. , Perheentupa A. , Virtanen H. E. , Skakkebæk N. E. , Toppari J. 
Published: March 2011

SummaryImpaired semen quality and testicular cancer may be linked through a testicular dysgenesis syndrome of foetal origin. The incidence of testis cancer has been shown to increase among Finnish men, whereas there is no recent publication describing temporal trends in semen quality. Therefore, we carried out a prospective semen quality study and a registry study of testis cancer incidence among Finnish men to explore recent trends. A total of 858 men were investigated in the semen quality study during 1998–2006. Median sperm concentrations were 67 (95% CI 57–80) million/mL, 60 (51–71) and 48 (39–60) for birth cohorts 1979–81, 1982–83 and 1987; total sperm counts 227 (189–272) million, 202 (170–240) and 165 (132–207); total number of morphologically normal spermatozoa 18 (14–23) million, 15 (12–19) and 11 (8–15). Men aged 10–59 years at the time of diagnosis with testicular cancer during 1954–2008 were included in the registry study, which confirmed the increasing incidence of testicular cancer in recent cohorts. These simultaneous and rapidly occurring adverse trends suggest that the underlying causes are environmental and, as such, preventable. Our findings necessitate not only further surveillance of male reproductive health but also research to detect and remove the underlying factors.
Registered Nurses’ smoking behaviours and their attitudes to personal cessation
Authors: Berkelmans Anna , Burton Debbie , Page Karen , Worrall‐Carter Linda 
Published: March 2011

berkelmans a., burton d., page k. & worrall‐carter l. (2011) Registered Nurses’ smoking behaviours and their attitudes to personal cessation. Journal of Advanced Nursing67(7), 1580–1590.AbstractAim.  The aim of the study was to assess smoking behaviour of nurses including; (1) smoking prevalence and nicotine dependence; (2) demographic characteristics according to smoking status and (3) attitudes to cessation amongst current smokers.Background.  Smoking amongst nurses is a barrier to the delivery of patient smoking cessation interventions. Studies on the smoking behaviour of nurses have lagged behind government surveys on smoking prevalence in the general population.Method.  A descriptive, comparative study using a self‐administered questionnaire was distributed to 3200 nurses over July and August of 2007 across one major metropolitan health service network in Victoria, Australia.Results.  The questionnaire was completed by 1029 nurses, a response rate of 32%. Eleven per cent of nurses (n = 113) were current smokers. Nurses who smoked were more likely to be divorced/separated and report smoking amongst family and friends. Smoking was more common amongst nurses who work in psychiatry and the emergency departments. Amongst the nurses who smoked, 45% desired to stop smoking and while 89% had experienced previous quit attempts, only half had ever received help or advice about smoking cessation. The most common factors preventing smoking cessation included fear of withdrawal symptoms including stress, weight gain and anxiety.Conclusion.  Smoking rates amongst nurses in this sample have declined below smoking rates amongst the general population. Considering the low uptake of smoking cessation support reported in this study, targeted strategies must be developed sensitive to the potential intrapersonal‐professional struggle related to personal smoking which is at odds with nurses’ health promotion role.
Breast cancer knowledge among women with intellectual disabilities and their experiences of receiving breast mammography
Authors: Truesdale‐Kennedy Maria , Taggart Laurence , McIlfatrick Sonja 
Published: March 2011

truesdale‐kennedy m., taggart l. & mcilfatrick s. (2011) Breast cancer knowledge among women with intellectual disabilities and their experiences of receiving breast mammography. Journal of Advanced Nursing67(6), 1294–1304.AbstractAim.  This paper is a report of a descriptive study of understanding of breast cancer and experiences of breast mammography among women with an intellectual disability.Background.  Despite the efforts of government policies and documents to ensure equal access to improve health screening for people with intellectual disability, the uptake for breast mammography in this population still remains lower than that of the general population.Method.  A qualitative approach using four focus groups was undertaken with 19 women identified as having a borderline to moderate intellectual disability all of whom had received a breast mammography. Data collection took place in 2009. Analysis of the data was undertaken using thematic content analysis.Results.  The women’s knowledge of breast cancer including associated risks, preventative factors and signs and symptoms were extremely limited with their sources of knowledge primarily coming from carers or nursing staff on receipt of an invitation for mammography. Although these women expressed a positive attitude towards their experiences of breast mammography, they also described negative feelings of fear and anxiety, attributed to a lack of understanding about the screening process. A lack of information and embarrassment were identified as the main barriers to screening for this group.Conclusion.  This study highlights the need for accessible multi‐format information in order to facilitate health promotion and education in women with intellectual disability, their family carers and healthcare staff working with this target group in order to enhance the knowledge and awareness of breast cancer and screening.