bluuebunny/crossref_metadata_2025 huggingface dataset:
Sex differences in the endocrine predictors of essential hypertension. Vasopressin versus renin.
Authors: Cowley A W , Skelton M M , Velasquez M T
Published: August 2012

The relationships between arterial pressure (BP) and plasma vasopressin levels, plasma renin activity, and other variables were determined in 96 untreated essential hypertensive men (146/100 mm Hg) and women (153/102 mm Hg) whose average age was 44 years, 80 normal men and women (121/79 mm Hg; mean age, 47 +/- 2 years), and 40 subjects defined as borderline hypertensive. An analysis of variance indicated significant sex differences in the population. Levels of plasma vasopressin were significantly elevated in hypertensive men, with 26% (high plasma vasopressin hypertensive) exhibiting levels greater than 2 SD of the normal mean, and multivariate regression analysis indicated a significant positive correlation between plasma vasopressin levels and systolic and diastolic blood pressure. Hypertensive men had a larger daily urine volume than normal men. Diastolic pressure and heart rate were significantly elevated in a subgroup of 12 weight-matched and age-matched hypertensive men in the high plasma vasopressin group compared with levels in normal plasma vasopressin hypertensive men. Hypertensive women had lower plasma renin activity than normal women, and multivariate analysis indicated a significant negative correlation between plasma renin activity and systolic and diastolic blood pressure. Other significant abnormalities in both sexes were noted: hypertensive men and women weighed more and excreted more sodium per day, and both had higher heart rates. With a discriminant analysis of 18 variables in male subjects, plasma vasopressin levels, urinary sodium excretion, and heart rate correctly classified 71% of normal and hypertensive subjects. In women, plasma renin activity, urinary sodium excretion, and heart rate correctly classified 77% of normal and hypertensive subjects. Despite the inability to ascertain causal relationships, the ability of the three variables in combination to correctly classify normal and hypertensive subjects indicates that these combined variables are reproducibly altered in persons with essential hypertension.
Role of the macula densa in renin release.
Authors: Itoh S , Carretero O A
Published: August 2012

To examine the role of the macula densa in renin release, afferent arterioles alone or afferent arterioles with the macula densa attached were microdissected from rabbit kidney and incubated in Medium 199 for two consecutive 30-minute periods. Renin concentration in the medium was measured using partially purified rabbit angiotensinogen. Renin release rate over 1 hour from a single arteriole (or an arteriole with macula densa) was calculated and expressed as nanograms of angiotensin I generated per hour per arteriole (or arteriole with macula densa) per hour incubation (ng of ANG I X hr-1 X Af-1/hour). Basal renin release rate from afferent arterioles was 0.69 +/- 0.13 ng of ANG I X hr-1 X Af-1/hour (mean +/- SEM, n = 9) and remained stable for 60 minutes. Basal renin release rate from arterioles with macula densa was 0.25 +/- 0.03 ng of ANG I X hr-1 X Af + MD-1/hour (n = 9), which was significantly lower (p less than 0.025) than that from afferent arterioles alone. When furosemide (1.5 X 10(-3) M) was added to afferent arterioles alone, no significant change in renin release was observed (percent change from control; 24.8 +/- 29.9%; p greater than 0.05, n = 6). When furosemide was added to arterioles with macula densa attached, however, renin release increased by 387 +/- 46% (n = 7; p less than 0.001). After pretreatment with indomethacin, a cyclooxygenase inhibitor, furosemide still increased renin release from 0.17 +/- 0.03 to 0.60 +/- 0.10 ng of ANG I X hr-1 X Af + MD-1/hour (n = 4; p less than 0.05); however, indomethacin pretreatment reduced both the basal renin release rate and the absolute change in renin release induced by furosemide. We conclude that (1) the macula densa inhibits renin release in this preparation, (2) the macula densa plays a central role in furosemide-induced renin release, and (3) while the prostaglandin system is not essential for furosemide-induced renin release, it may be a modulating factor.
Plasma chromogranin A. Initial studies in human hypertension.
Authors: O'Connor D T
Published: August 2012

Chromogranin A is the major catecholamine storage vesicle soluble protein costored and coreleased by exocytosis with catecholamines. Immunoreactive chromogranin A circulates in human plasma, where it may reflect changes in exocytotic sympathoadrenal activity. We measured plasma chromogranin A concentration in normotensive control subjects as well as in untreated essential (primary) hypertensive subjects and subjects with several varieties of secondary hypertension. Plasma chromogranin A concentration was higher in subjects with essential hypertension (n = 32) than in normal controls (n = 18; 198 +/- 32 versus 129 +/- 12 ng/ml [mean +/- SEM]; p less than 0.05), and was also elevated in subjects with hypertension secondary to renal parenchymal disease (n = 9; 192 +/- 36 ng/ml; 0.05 less than p less than 0.1) and those with pheochromocytoma (n = 11; 1614 +/- 408 ng/ml; p less than 0.01). In essential hypertensive subjects (n = 5), short-term suppression of sympathetic outflow with oral guanabenz (4 mg) reduced plasma chromogranin A concentration within 30 to 60 minutes, while the blood pressure response was more gradual and was maximal at 3 hours. The results suggest that plasma chromogranin A is, at least in part, under neural control and that there may be an excess of exocytotic sympathoadrenal activity in essential hypertension. These initial studies are now being expanded to larger subject groups.
Highly potent and specific inhibitors of human renin.
Authors: Kokubu T , Hiwada K , Murakami E , Imamura Y , Matsueda R , Yabe Y , Koike H , Iijima Y
Published: August 2012

Small peptide analogues representing the C-terminal portion of angiotensin I sequence were designed as inhibitors of human renin. Among synthesized compounds, benzyloxycarbonyl (-"Z")-(1-naphthyl)Ala-His-leucinal (ES-188), Z-(1-naphthyl)Ala-His-statine ethyl ester (ES-226), and Z-(1-naphthyl)Ala-His-statine 2-methylbutylamide (ES-254) markedly inhibited human and primate renins (inhibitory concentration, 50% [IC50], near 10(-7) M). These peptide analogues inhibited rabbit renin with one or two orders of magnitude less potency. They were very weak inhibitors of renins from pig, goat, dog, and rat. ES-188 had no discernible effect on cathepsin D, pepsin, or human angiotensin-converting enzyme at the concentration of 10(-4)M. ES-226 had little effect on the three enzymes at the concentration of 10(-5)M; however, ES-254 had a considerable inhibitory effect on cathepsin D (IC50 of 1.4 X 10(-5)M), pepsin (IC50 of 4.2 X 10(-5)M), and human angiotensin-converting enzyme (IC50 of 7.1 X 10(-6)M). Our results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors.
Simultaneous Control of Diabetes Mellitus, Hypertension, and Hyperlipidemia in 2 Health Systems
Authors: Schroeder Emily B. , Hanratty Rebecca , Beaty Brenda L. , Bayliss Elizabeth A. , Havranek Edward P. , Steiner John F.
Published: August 2012

Background—

Many individuals with diabetes mellitus, hypertension, and hyperlipidemia have difficulty achieving control of all 3 conditions. We assessed the incidence and duration of simultaneous control of hyperglycemia, blood pressure, and low-density lipoprotein cholesterol in patients from 2 health care systems in Colorado.

Methods and Results—

We performed a retrospective cohort study of adults at Denver Health and Kaiser Permanente Colorado with diabetes mellitus, hypertension, and hyperlipidemia from 2000 through 2008. Over a median of 4.0 and 4.4 years, 16% and 30% of individuals at Denver Health and Kaiser Permanente achieved the primary outcome (simultaneous control with a glycosylated hemoglobin (HbA
1c
) <7.0%, blood pressure <130/80 mm Hg, and low-density lipoprotein cholesterol <100 mg/dL), respectively. With less strict goals (HbA
1c
<8.0%, blood pressure <140/90 mm Hg, and low-density lipoprotein cholesterol <130 mg/dL), 44% and 70% of individuals at Denver Health and Kaiser Permanente achieved simultaneous control. Sociodemographic characteristics (increasing age, white ethnicity), and the presence of cardiovascular disease or other comorbidities were significantly but not strongly predictive of achieving simultaneous control in multivariable models. Simultaneous control was less likely as severity of the underlying conditions increased, and more likely as medication adherence increased.

Conclusions—

Simultaneous control of diabetes mellitus, hypertension, and hyperlipidemia was uncommon and generally transient. Less stringent goals had a relatively large effect on the proportion achieving simultaneous control. Individuals who simultaneously achieve multiple treatment goals may provide insight into self-care strategies for individuals with comorbid health conditions.
Bionic Baroreceptor Corrects Postural Hypotension in Rats With Impaired Baroreceptor
Authors: Hosokawa Kazuya , Ide Tomomi , Tobushi Tomoyuki , Sakamoto Kazuo , Onitsuka Ken , Sakamoto Takafumi , Fujino Takeo , Saku Keita , Sunagawa Kenji
Published: August 2012

Background—

Impairment of the arterial baroreflex causes orthostatic hypotension. Arterial baroreceptor sensitivity degrades with age. Thus, an impaired baroreceptor plays a pivotal role in orthostatic hypotension in most elderly patients. There is no effective treatment for orthostatic hypotension. The aims of this investigation were to develop a bionic baroreceptor (BBR) and to verify whether it corrects postural hypotension.

Methods and Results—

The BBR consists of a pressure sensor, a regulator, and a neurostimulator. In 35 Sprague-Dawley rats, we vascularly and neurally isolated the baroreceptor regions and attached electrodes to the aortic depressor nerve for stimulation. To mimic impaired baroreceptors, we maintained intracarotid sinus pressure at 60 mm Hg during activation of the BBR. Native baroreflex was reproduced by matching intracarotid sinus pressure to the instantaneous pulsatile aortic pressure. The encoding rule for translating intracarotid sinus pressure into stimulation of the aortic depressor nerve was identified by a white noise technique and applied to the regulator. The open-loop arterial pressure response to intracarotid sinus pressure (n=7) and upright tilt–induced changes in arterial pressure (n=7) were compared between native baroreceptor and BBR conditions. The intracarotid sinus pressure–arterial pressure relationships were comparable. Compared with the absence of baroreflex, the BBR corrected tilt-induced hypotension as effectively as under native baroreceptor conditions (native, −39±5 mm Hg; BBR, −41±5 mm Hg; absence, −63±5 mm Hg;
P
<0.05).

Conclusions—

The BBR restores the pressure buffering function. Although this research demonstrated feasibility of the BBR, further research is needed to verify its long-term effect and safety in larger animal models and humans.
Retrospective Multicenter Study of Solitaire FR for Revascularization in the Treatment of Acute Ischemic Stroke
Authors: Dávalos Antoni , Pereira Vitor Mendes , Chapot René , Bonafé Alain , Andersson Tommy , Gralla Jan
Published: August 2012

Background and Purpose—

The purpose of this study was to evaluate safety and efficacy of the Solitaire FR device in the treatment of patients with acute ischemic stroke secondary to large artery occlusion.

Methods—

We conducted a retrospective study of consecutive patients presenting with acute ischemic stroke treated with Solitaire FR as the first-line device to restore blood flow in 6 experienced European centers. This study was entirely funded and supported by Coviden Neurovascular. An independent Corelab determined modified Thrombolysis in Cerebral Infarction scores on the preprocedure and postprocedure angiograms. Complete revascularization was defined as modified Thrombolysis in Cerebral Infarction 2b or 3 post-Solitaire FR device use. Symptomatic intracranial hemorrhage was defined as parenchymal hemorrhage Type 2 associated with a decline of ≥4 points in the National Institutes of Health Stroke Scale score within 24 hours or causing death. Favorable functional outcome was considered as modified Rankin Scale score ≤2 at Day 90.

Results—

We studied 141 patients (mean age, 66 years; median National Institutes of Health Stroke Scale, 18); 74 patients received intravenous tissue-type plasminogen activator before endovascular treatment. Complete revascularization was achieved in 120 of 142 occlusion sites (85%) and good outcome in 77 of 141 (55%) patients. Good outcome was more frequent in patients treated with intravenous tissue-type plasminogen activator than in those without (66% versus 42%;
P
<0.01). Symptomatic intracranial hemorrhage was reported in 5 patients (4%) and 29 of 141 (20%) patients died or were lost during follow-up (3 cases).

Conclusions—

This retrospective study with centralized evaluation shows that the use of Solitaire FR is safe and achieves good revascularization rates and functional outcomes in patients with acute ischemic stroke and large artery occlusion.
Do questions written in the target language make foreign language listening comprehension tests more difficult?
Authors: Filipi Anna
Published: August 2012

The Assessment of Language Competence (ALC) certificates is an annual, international testing program developed by the Australian Council for Educational Research to test the listening and reading comprehension skills of lower to middle year levels of secondary school. The tests are developed for three levels in French, German, Italian and Japanese, and at two levels in Chinese and Indonesian. There is a mixture of target language and English questions in the Level 2 and 3 tests. Some teachers have raised this as a concern in the belief that all questions should only be offered in English for the sake of fairness. Their view is that the tests are unduly difficult when they are designed with questions in the language. Arising from this concern, the aim of the research to be reported in this paper was to investigate the effects of the language of the question on student performance. We drew on data from a trial test and a final listening test, a questionnaire administered to students to gauge their perceptions of the tests and an examination of public documentation about the ALC. For the statistical analysis, we used Item Response Theory for calibrating items and for comparing item difficulty estimates, and fit statistics to verify how well items with English and target language question formats worked together. We found that where the questions involved listening for simple, explicitly stated information, students found the items in the target language relatively easier. In questions that required students to listen for global meaning, language choice either did not matter or tended to favour items in English rather than the target language. Furthermore, each of the six tests with some items in English and others in the target language showed a high level of reliability and fit to the single latent scale, indicating that items were functioning consistently regardless of the language of the test question.
Transformations in kinship, land rights and social boundaries among the Wampar in Papua New Guinea and the generative agency of children of interethnic marriages
Authors: Schwörer Doris Bacalzo
Published: August 2012

Among the Wampar in Papua New Guinea, children are active participants in the dynamics of kinship and identity construction. This article explores the transformative capabilities of children of interethnic marriages, particularly those with non-Wampar fathers. It examines children’s notions of belonging and rights through their practices and engagement in the discourses on social boundaries of kinship and ethnicity. Amid changing economic conditions that foster tightening of kinship boundaries and restrictions on land rights, children, who are valued as social capital, shift the balance towards mutuality of rights and benefits. Moreover, they further fluidity in reckoning kinship and the ordering of social relations.
Lateral forces on tapered pistons – An overview
Authors: Urata Eizo
Published: August 2012

The purpose of this article is to contribute to a more comprehensive overview of the lateral force on tapered pistons. Numerical analyses are carried out to evaluate the lateral force on a piston; the flow rate through the clearance is also calculated. The range of parameters, namely, length-to-diameter ratio, the taper and the eccentricity, covers almost all the applications that appear in fluid power engineering. The pressure distribution obtained by difference equations is verified using an iteration convergence test. The lateral force is obtained applying Simpson’s integral to the obtained pressure. Using the dimensionless lateral forces obtained using finite mesh sizes, an evaluation of the dimensionless lateral force for an infinitely fine mesh size is made. The numerical results coincide well with experiments reported in the literature. An approximate function is shown by expressing the dimensionless force with an accuracy of about 3% for a region of the taper and the length/diameter ratio appearing frequently in practice. Four types of difference equations that are derived from the laminar flow equation are compared with respect to necessary iteration numbers and accuracy of the results.
The modification of a slip resistance meter for measurement of railhead adhesion
Authors: Lewis Roger , Lewis Stephen R , Zhu Yi , Abbasi Saeed , Olofsson Ulf
Published: August 2012

The aim of this work was to find a quick, flexible and localised method for determining railhead adhesion. The proposed method is a pendulum rig, which has a rubber pad at the base of a swinging arm. The arm is released and as the rubber pad slides across the contact surface, energy is lost. This loss can be translated into a friction coefficient. Tests have been performed under dry and contaminated conditions, including water, oil and leaf layers both in the laboratory on extracted rail and in the field on live rail. Friction modifiers were also tested. The results of these tests are compared with data obtained using a hand-pushed tribometer. The performed study shows that the pendulum is a viable way to test adhesion levels in the field.
Identification of seven water-soluble non-storage proteins from pomegranate (Punica granatum Linn.) seeds
Authors: Yang Haixia , Li Meiliang , Qi Xin , Lv Chenyan , Deng Jianjun , Zhao Guanghua
Published: August 2012

As pomegranate ( Punica granatum Linn.) processing is fast growing, the usage of pomegranate processing wastes containing seeds has been receiving great attention. The protein component accounts for 100–130 g/kg of the seeds in weight. However, so far, there is no information on the composition and function of the pomegranate seed proteins. In this study, a global view of water-soluble non-storage proteins isolated from mature pomegranate seeds were studied using two-dimensional polyacrylamide gel electrophoresis coupled with liquid chromatography–tandem mass spectrometry. With the two-dimensional polyacrylamide gel electrophoresis approach, over 120 protein spots were resolved, of which 7 abundant protein spots showing low molecular mass were identified. These identified proteins may be linked to seed development and metabolism, but more importantly, the occurrence of these proteins provides the possibility of conversion the pomegranate processing wastes into useful products or raw material for food industry.
Adjustment of Time Perception in the Range of Seconds and Milliseconds
Authors: Walg Marco , Oepen Johannes , Prior Helmut
Published: August 2012

Objective: The nature of time-processing alterations in ADHD was assessed by means of duration judgments and temporal set-shifting tasks lasting several seconds and milliseconds. Method: After training with visual sample stimuli for long and short durations, 31 children with ADHD and 29 controls estimated the durations of test stimuli. During testing, the temporal context was systematically varied by shifting the duration of stimulus sets to longer or shorter intervals. Results: Children with ADHD generally overestimated the durations of stimuli on the seconds scale. Their assessment of stimuli on the milliseconds scale can be characterized as less-efficient adaptations to new temporal sets alongside otherwise normal discrimination performance. Conclusion: Findings support a pure time perception alteration in ADHD. In addition, results provide first evidence that difficulties in mental set-shifting, which have been reported for other tasks, extend to temporal processing in children with ADHD.
Publication Bias in the Organizational Sciences
Authors: Kepes Sven , Banks George C. , McDaniel Michael , Whetzel Deborah L.
Published: August 2012

Publication bias poses multiple threats to the accuracy of meta-analytically derived effect sizes and related statistics. Unfortunately, a review of the literature indicates that unlike meta-analytic reviews in medicine, research in the organizational sciences tends to pay little attention to this issue. In this article, the authors introduce advances in meta-analytic techniques from the medical and related sciences for a comprehensive assessment and evaluation of publication bias. The authors illustrate their use on a data set on employment interview validities. Using multiple methods, including contour-enhanced funnel plots, trim and fill, Egger’s test of the intercept, Begg and Mazumdar’s rank correlation, meta-regression, cumulative meta-analysis, and selection models, the authors find limited evidence of publication bias in the studied data.
Glutamate gene polymorphisms predict brain volumes in multiple sclerosis
Authors: Strijbis Eva MM , Inkster Becky , Vounou Maria , Naegelin Yvonne , Kappos Ludwig , Radue Ernst-Wilhelm , Matthews Paul M , Uitdehaag Bernard MJ , Barkhof Frederik , Polman Chris H , Montana Giovanni , Geurts Jeroen JG
Published: August 2012

Background:

Several genetic markers have been associated with multiple sclerosis (MS) susceptibility; however, uncovering the genetic aetiology of the complex phenotypic expression of MS has been more difficult so far. The most common approach in imaging genetics is based on mass-univariate linear modelling (MULM), which faces several limitations.

Objective:

Here we apply a novel multivariate statistical model, sparse reduced-rank regression (sRRR), to identify possible associations of glutamate related single nucleotide polymorphisms (SNPs) and multiple MRI-derived phenotypes in MS.

Methods:

Seven phenotypes related to brain and lesion volumes for a total number of 326 relapsing–remitting and secondary-progressive MS patients and a total of 3809 glutamate related and control SNPs were analysed with sRRR, which resulted in a ranking of SNPs in decreasing order of importance (‘selection probability’). Lasso regression and MULM were used as comparative statistical techniques to assess consistency of the most important associations over different statistical models.

Results:

Five SNPs within the NMDA-receptor-2A-subunit (GRIN2A) domain were identified by sRRR in association with normalized brain volume (NBV), normalized grey matter volume and normalized white matter volume (NMWM). The association between GRIN2A and both NBV and NWMV was confirmed in MULM and Lasso analysis.

Conclusions:

Using a novel, multivariate regression model confirmed by two other statistical approaches we show associations between GRIN2A SNPs and phenotypic variation in NBV and NWMV in this first exploratory study. Replications in independent datasets are now necessary to validate these findings.
Governance through norms and standards: The normative force behind design-led crime prevention
Authors: Stummvoll Günter
Published: August 2012

Crime prevention standards in housing have for a long time been limited to target hardening, and in that respect European Norms were developed as guidelines for ‘burglar resistant’ doors, windows and shutters (EN1630). Recent developments include a set of supplementary crime prevention standards in the building sector, which are not limited to technical products but focus on the layout and management of urban environments and their impact on public safety. This article focuses on the problem of systematic Europe-wide implementation of crime prevention standards in urban planning. The attempt to implement common guidelines for design-led crime prevention through the development of a European Norm has failed. In this article I will first introduce the system of standardization and then examine the particular European Standard for Crime Prevention by Urban Planning and Building Design (CEN/TR14383). Instead of a harmonious application of that standard in Europe, a variety of policies have been negotiated, including national standardization, consulting schemes and liaison systems based on rewards. Moreover the standard has been re-interpreted in some jurisdictions as ‘gender mainstreaming’, and it has been adopted by police to organize national training for local governments. I will present and compare examples from Denmark, the UK, the Netherlands, Austria and Poland to show the divergent ways of interpretation and practical implementation of guidelines in design-led crime prevention.
Attenuation of endoplasmic reticulum stress and mitochondrial injury in kidney with ischemic postconditioning application and trimetazidine treatment
Authors: Mahfoudh-Boussaid Asma , Zaouali Mohamed Amine , Hauet Thierry , Hadj-Ayed Kaouther , Miled Abdel-Hédi , Ghoul-Mazgar Sonia , Saidane-Mosbahi Dalila , Rosello-Catafau Joan , Abdennebi Hassen Ben
Published: August 2012

Background

Endoplasmic reticulum (ER) and mitochondria have been implicated in the pathology of renal ischemia/reperfusion (I/R). In the present study, we investigated whether the use of ischemic postconditioning (IPostC) and trimetazidine (TMZ) separately or combined could reduce ER stress and mitochondria damage after renal ischemia.

Methods

Kidneys of Wistar rats were subjected to 60-min of warm ischemia followed by 120-min of reperfusion (I/R group, n = 6), or to 6 cycles of ischemia/reperfusion (10-s each cycle) just after 60-min of warm ischemia (IPostC group, n = 6), or to i.p. injection of TMZ (3 mg/kg) 30-min before ischemia (TMZ group, n = 6), or to the combination of both treatments (IPostC+TMZ group, n = 6). The results of these experimental groups were compared to those of a sham-operated group in which rat renal pedicles were only dissected. Sodium reabsorption rate, creatinine clearance lactate deshydrogenase (LDH) activity in plasma, and concentration of malonedialdehyde (MDA) in tissue were determined. In addition, Western blot analysis was performed to identify the amounts of cytochrome c, c-JunNH2-terminal kinase (JNK), voltage-dependent anion channel (VDAC), glycogen synthase kinase 3-beta (GSK3-β), and ER stress parameters.

Results

IPostC or/and TMZ significantly decreased cytolysis, oxidative stress and improved renal function in comparison to I/R group. IPostC but not TMZ significantly attenuated ER stress parameters versus I/R group. Indeed, it down-regulated the glucose-regulated protein 78 (GRP78), the activating transcription factor 4 (ATF4), the RNA activated protein kinase (PKR)-like ER kinas (PERK), the X box binding protein-1 (XBP-1) and the caspase12 protein levels. TMZ treatment significantly augmented GSK3-β phosphorylation and reduced levels of cytochrome c and VDAC phosphorylation in comparison to IPostC application. The combination of both treatments gave a synergetic effect. It significantly improved the survival rate, attenuated cytolysis, oxidative stress and improved renal function.

Conclusion

This study revealed that IPostC protects kidney from I/R injury by suppressing ER stress while the beneficial effects of TMZ are mediated by mitochondria protection. The combination of both treatments ameliorated functional recovery.
Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak
Authors: Corogeanu Diana , Willmes Ruben , Wolke Martina , Plum Georg , Utermöhlen Olaf , Krönke Martin
Published: August 2012

Background

The shiga toxin-producing E. coli (STEC) O104:H4 caused a major outbreak in Germany in spring 2011. STEC are usually susceptible to common antibiotics. However, antibiotic treatment of STEC-infected patients is not recommended because STEC may enhance production and release of shiga toxins (STX) in response to antibiotics, which eventually enhances the frequency and severity of clinical symptoms, including haemolytic uraemic syndrome (HUS) and fatalities.

Results

We characterized the response to antibiotics of STEC O104:H4 isolates from two HUS patients during the German STEC outbreak in spring 2011 in comparison to the common STEC O157:H7. Liquid cultures of STEC O157:H7 and O104:H4 were incubated with graded dilutions of the antibiotics ciprofloxacin, meropenem, fosfomycin, gentamicin, rifampicin, and chloramphenicol. At defined times of antibiotic treatment, transcriptional activation of the STX2 gene, contents of STX and STX-activity in the culture supernatants were quantified. Unlike the common serotype O157:H7, STEC O104:H4 does not release STX in response to therapeutic concentrations of ciprofloxacin, meropenem, fosfomycin, and chloramphenicol.

Conclusions

In future outbreaks, the response of the respective epidemiologic STEC strain to antibiotics should be rapidly characterized in order to identify antibiotics that do not enhance the release of STX. This will eventually allow clinical studies tackling the question whether antibiotic treatment impacts on the eradication of STEC, clinical course of disease, and frequency of carriers.
Peri-operative chemotherapy in the management of resectable colorectal cancer pulmonary metastases
Authors: Hawkes Eliza A , Ladas George , Cunningham David , Nicholson Andrew G , Wassilew Katharina , Barbachano Yolanda , Ratnayake Gihan , Rao Sheela , Chau Ian
Published: August 2012

Background

Surgery is often advocated in patients with resectable pulmonary metastases from colorectal cancer (CRC). Our study aims to evaluate peri-operative chemotherapy in patients with metastastic CRC undergoing pulmonary metastasectomy.

Methods

Patients treated for CRC who underwent pulmonary metastasectomy by a single surgeon were identified. Outcome measures included survival, peri-operative complications, radiological and histological evidence of chemotherapy-induced lung toxicities.

Results

Between 1997 and 2009, 51 eligible patients were identified undergoing a total of 72 pulmonary resections. Thirty-eight patients received peri-operative chemotherapy, of whom 9 received an additional biological agent. Five-year overall survival rate was 72% in the whole cohort - 74% and 68% in those who received peri-operative chemotherapy (CS) and those who underwent surgery alone (S) respectively. Five-year relapse free survival rate was 31% in the whole cohort - 38% and ≤18% in CS and S groups respectively. Only 8% had disease progression during neoadjuvant chemotherapy. There were no post-operative deaths. Surgical complications occurred in only 4% of patients who received pre-operative chemotherapy. There was neither radiological nor histological evidence of lung toxicity in resected surgical specimens.

Conclusions

Peri-operative chemotherapy can be safely delivered to CRC patients undergoing pulmonary metastasectomy. Survival in this selected group of patients was favourable.
Understanding how adherence goals promote adherence behaviours: a repeated measure observational study with HIV seropositive patients
Authors: Jones Gareth , Hawkins Kim , Mullin Rebecca , Nepusz Tamás , Naughton Declan P , Sheeran Paschal , Petróczi Andrea
Published: August 2012

Background

The extent to which patients follow treatments as prescribed is pivotal to treatment success. An exceptionally high level (> 95%) of HIV medication adherence is required to suppress viral replication and protect the immune system and a similarly high level (> 80%) of adherence has also been suggested in order to benefit from prescribed exercise programmes. However, in clinical practice, adherence to both often falls below the desirable level. This project aims to investigate a wide range of psychological and personality factors that may lead to adherence/non-adherence to medical treatment and exercise programmes.

Methods

HIV positive patients who are referred to the physiotherapist-led 10-week exercise programme as part of the standard care are continuously recruited. Data on social cognitive variables (attitude, intention, subjective norms, self-efficacy, and outcome beliefs) about the goal and specific behaviours, selected personality factors, perceived quality of life, physical activity, self-reported adherence and physical assessment are collected at baseline, at the end of the exercise programme and again 3 months later. The project incorporates objective measures of both exercise (attendance log and improvement in physical measures such as improved fitness level, weight loss, improved circumferential anthropometric measures) and medication adherence (verified by non-invasive hair analysis).

Discussion

The novelty of this project comes from two key aspects, complemented with objective information on exercise and medication adherence. The project assesses beliefs about both the underlying goal such as following prescribed treatment; and about the specific behaviours such as undertaking the exercise or taking the medication, using both implicit and explicit assessments of patients’ beliefs and attitudes. We predict that i) the way people think about the underlying goal of their treatments explains medication and exercise behaviours over and above the effects of the behaviour-specific thinking and ii) the relationship between adherence to exercise and to medical treatment is stronger among those with more favourable views about the goal. Results from this study should identify the key contributing factors to inform subsequent adherence research and afford a more streamlined assessment matrix. The project also aims to inform patient care practices.

UK Clinical Research Network registration number

UKCRN 7842.
Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury
Authors: Van der Mieren Gerry , Nevelsteen Ines , Vanderper Annelies , Oosterlinck Wouter , Flameng Willem , Herijgers Paul
Published: August 2012

Background

The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.

Methods

C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student’s t-test or factorial ANOVA followed by a Fisher’s LSD post hoc test.

Results

Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.

Conclusion

ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.
Regulation of Toll-like receptor 4-mediated immune responses through Pasteurella multocida toxin-induced G protein signalling
Authors: Hildebrand Dagmar , Sahr Aline , Wölfle Sabine J , Heeg Klaus , Kubatzky Katharina F
Published: August 2012

Background

Lipopolysaccharide (LPS)-triggered Toll-like receptor (TLR) 4-signalling belongs to the key innate defence mechanisms upon infection with Gram-negative bacteria and triggers the subsequent activation of adaptive immunity. There is an active crosstalk between TLR4-mediated and other signalling cascades to secure an effective immune response, but also to prevent excessive inflammation. Many pathogens induce signalling cascades via secreted factors that interfere with TLR signalling to modify and presumably escape the host response. In this context heterotrimeric G proteins and their coupled receptors have been recognized as major cellular targets. Toxigenic strains of Gram-negativePasteurella multocidaproduce a toxin (PMT) that constitutively activates the heterotrimeric G proteins Gαq, Gα13and Gαiindependently of G protein-coupled receptors through deamidation. PMT is known to induce signalling events involved in cell proliferation, cell survival and cytoskeleton rearrangement.

Results

Here we show that the activation of heterotrimeric G proteins through PMT suppresses LPS-stimulated IL-12p40 production and eventually impairs the T cell-activating ability of LPS-treated monocytes. This inhibition of TLR4-induced IL-12p40 expression is mediated by Gαi-triggered signalling as well as by Gβγ-dependent activation of PI3kinase and JNK.

Taken together we propose the following model: LPS stimulates TLR4-mediated activation of the NFĸB-pathway and thereby the production of TNF-α, IL-6 and IL-12p40. PMT inhibits the production of IL-12p40 by Gαi-mediated inhibition of adenylate cyclase and cAMP accumulation and by Gβγ-mediated activation of PI3kinase and JNK activation.

Conclusions

On the basis of the experiments with PMT this study gives an example of a pathogen-induced interaction between G protein-mediated and TLR4-triggered signalling and illustrates how a bacterial toxin is able to interfere with the host’s immune response.
Nicotine patches and quitline counseling to help hospitalized smokers stay quit: study protocol for a randomized controlled trial
Authors: Cummins Sharon , Zhu Shu-Hong , Gamst Anthony , Kirby Carrie , Brandstein Kendra , Klonoff-Cohen Hillary , Chaplin Edward , Morris Timothy , Seymann Gregory , Lee Joshua
Published: August 2012

Background

Hospitalized smokers often quit smoking, voluntarily or involuntarily; most relapse soon after discharge. Extended follow-up counseling can help prevent relapse. However, it is difficult for hospitals to provide follow-up and smokers rarely leave the hospital with quitting aids (for example, nicotine patches). This study aims to test a practical model in which hospitals work with a state cessation quitline. Hospital staff briefly intervene with smokers at bedside and refer them to the quitline. Depending on assigned condition, smokers may receive nicotine patches at discharge or extended quitline telephone counseling post-discharge. This project establishes a practical model that lends itself to broader dissemination, while testing the effectiveness of the interventions in a rigorous randomized trial.

Methods/design

This randomized clinical trial (N = 1,640) tests the effect of two interventions on long-term quit rates of hospitalized smokers in a 2 x 2 factorial design. The interventions are (1) nicotine patches (eight-week, step down program) dispensed at discharge and (2) proactive telephone counseling provided by the state quitline after discharge. Subjects are randomly assigned into: usual care, nicotine patches, telephone counseling, or both patches and counseling. It is hypothesized that patches and counseling have independent effects and their combined effect is greater than either alone. The primary outcome measure is thirty-day abstinence at six months; a secondary outcome is biochemically validated smoking status. Cost-effectiveness analysis is conducted to compare each intervention condition (patch alone, counseling alone, and combined interventions) against the usual care condition. Further, this study examines whether smokers’ medical diagnosis is a moderator of treatment effect. Generalized linear (binomial) mixed models will be used to study the effect of treatment on abstinence rates. Clustering is accounted for with hospital-specific random effects.

Discussion

If this model is effective, quitlines across the U.S. could work with interested hospitals to set up similar systems. Hospital accreditation standards related to tobacco cessation performance measures require follow-up after discharge and provide additional incentive for hospitals to work with quitlines. The ubiquity of quitlines, combined with the consistency of quitline counseling delivery as centralized state operations, make this partnership attractive.

Trial registration

Smoking cessation in hospitalized smokers NCT01289275. Date of registration February 1, 2011; date of first patient August 3, 2011.
Early prediction of histopathological response of rectal tumors after one week of preoperative radiochemotherapy using 18 F-FDG PET-CT imaging. A prospective clinical study
Authors: Goldberg Natalia , Kundel Yulia , Purim Ofer , Bernstine Hanna , Gordon Noa , Morgenstern Sara , Idelevich Efraim , Wasserberg Nir , Sulkes Aaron , Groshar David , Brenner Baruch
Published: August 2012

Background

Preoperative radiochemotherapy (RCT) is standard in locally advanced rectal cancer (LARC). Initial data suggest that the tumor’s metabolic response, i.e. reduction of its 18 F-FDG uptake compared with the baseline, observed after two weeks of RCT, may correlate with histopathological response. This prospective study evaluated the ability of a very early metabolic response, seen after only one week of RCT, to predict the histopathological response to treatment.

Methods

Twenty patients with LARC who received standard RCT regimen followed by radical surgery participated in this study. Maximum standardized uptake value (SUV-MAX), measured by PET-CT imaging at baseline and on day 8 of RCT, and the changes in FDG uptake (ΔSUV-MAX), were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and by achievement of pathological complete response (pCR).

Results

Absolute SUV-MAX values at both time points did not correlate with histopathological response. However, patients with pCR had a larger drop in SUV-MAX after one week of RCT (median: -35.31% vs −18.42%, p = 0.046). In contrast, TRG did not correlate with ΔSUV-MAX. The changes in FGD-uptake predicted accurately the achievement of pCR: only patients with a decrease of more than 32% in SUV-MAX had pCR while none of those whose tumors did not show any decrease in SUV-MAX had pCR.

Conclusions

A decrease in ΔSUV-MAX after only one week of RCT for LARC may be able to predict the achievement of pCR in the post-RCT surgical specimen. Validation in a larger independent cohort is planned.
A coarse-grained model for synergistic action of multiple enzymes on cellulose
Authors: Asztalos Andrea , Daniels Marcus , Sethi Anurag , Shen Tongye , Langan Paul , Redondo Antonio , Gnanakaran Sandrasegaram
Published: August 2012

Background

Degradation of cellulose to glucose requires the cooperative action of three classes of enzymes, collectively known as cellulases. Endoglucanases randomly bind to cellulose surfaces and generate new chain ends by hydrolyzing β-1,4-D-glycosidic bonds. Exoglucanases bind to free chain ends and hydrolyze glycosidic bonds in a processive manner releasing cellobiose units. Then, β-glucosidases hydrolyze soluble cellobiose to glucose. Optimal synergistic action of these enzymes is essential for efficient digestion of cellulose. Experiments show that as hydrolysis proceeds and the cellulose substrate becomes more heterogeneous, the overall degradation slows down. As catalysis occurs on the surface of crystalline cellulose, several factors affect the overall hydrolysis. Therefore, spatial models of cellulose degradation must capture effects such as enzyme crowding and surface heterogeneity, which have been shown to lead to a reduction in hydrolysis rates.

Results

We present a coarse-grained stochastic model for capturing the key events associated with the enzymatic degradation of cellulose at the mesoscopic level. This functional model accounts for the mobility and action of a single cellulase enzyme as well as the synergy of multiple endo- and exo-cellulases on a cellulose surface. The quantitative description of cellulose degradation is calculated on a spatial model by including free and bound states of both endo- and exo-cellulases with explicit reactive surface terms (e.g., hydrogen bond breaking, covalent bond cleavages) and corresponding reaction rates. The dynamical evolution of the system is simulated by including physical interactions between cellulases and cellulose.

Conclusions

Our coarse-grained model reproduces the qualitative behavior of endoglucanases and exoglucanases by accounting for the spatial heterogeneity of the cellulose surface as well as other spatial factors such as enzyme crowding. Importantly, it captures the endo-exo synergism of cellulase enzyme cocktails. This model constitutes a critical step towards testing hypotheses and understanding approaches for maximizing synergy and substrate properties with a goal of cost effective enzymatic hydrolysis.
Diabetic angiopathy and angiogenic defects
Authors: Xu Ling , Kanasaki Keizo , Kitada Munehiro , Koya Daisuke
Published: August 2012

Diabetes is one of the most serious health problems in the world. A major complication of diabetes is blood vessel disease, termed angiopathy, which is characterized by abnormal angiogenesis. In this review, we focus on angiogenesis abnormalities in diabetic complications and discuss its benefits and drawbacks as a therapeutic target for diabetic vascular complications. Additionally, we discuss glucose metabolism defects that are associated with abnormal angiogenesis in atypical diabetic complications such as cancer.