bluuebunny/crossref_metadata_2025 huggingface dataset:
Injury risk in Danish youth and senior elite handball using a new SMS text messages approach
Authors: Moller Merete , Attermann Jorn , Myklebust Grethe , Wedderkopp Niels
Published: June 2012

Objective

To assess the injury incidence in elite handball, and if gender and previous injuries are risk factors for new injuries.

Methods

Cohort study of 517 male and female elite handball players (age groups under (u)16, u-18 and senior). Participants completed a web survey establishing injury history, demographic information and sports experience, and provided weekly reports of time-loss injuries and handball exposure for 31 weeks by short message service text messaging (SMS). Injuries were further classified by telephone interview.

Results

The weekly response rate ranged from 85% to 90% illustrating the promise of the SMS system as a tool in injury surveillance. Of 448 reported injuries, 165 injuries (37%) were overuse injuries and 283 (63%) traumatic injuries. Knee (19%) and ankle (29%) were the most common traumatic injuries. The injury incidence during match play was 23.5 (95% CI 17.8 to 30.4), 15.1 (95% CI 9.7 to 22.2), 11.1 (95% CI 7.0 to 16.6) injuries per 1000 match hours among senior, u-18 and u-16 players, respectively. U-18 male players had an overall 1.76 (95% CI 1.10 to 2.80) times higher risk of injury compared to females. Having had two or more previous injuries causing absence from handball for more than 4 weeks increased the risk of new injury in the u-16 group (IRR: 1.79 (95% CI 1.03 to 3.11)–2.23 (95% CI 1.22 to 4.10)).

Conclusion

The incidence of time-loss injuries in elite handball was higher during match play than previously reported in recreational handball. Previous injuries were a risk factor for new injuries among u-16 players. Male players had a significant higher injury rate in the u-18 group.
Paediatric palliative care: a survey of paediatricians and family practitioners
Authors: Straatman Lynn , Miller Tanice
Published: June 2012

Background

Paediatric palliative care focuses on the enhancement of the quality of life for a child and family through a combination of active and compassionate therapies intended to comfort and support the child and family who are living with a life-threatening illness. The purpose of this study was to assess the experience with and confidence in providing paediatric palliative care of practicing family/general practitioners (GPs) and paediatricians. In addition, the learning needs, modes of learning and their methods of coping/self-care were questioned.

Methods

Two hundred paediatricians and GPs in the province of British Columbia were randomly selected to participate in a mailed survey. The survey consisted of three categories: demographic information, experience and knowledge of paediatric palliative care, educational needs and preferences for learning and provision of their own self-care.

Results

The response rate of completed surveys was 56.5%. Only 40.1% of respondents felt their knowledge and experience were adequate. Overall, 73.5% of the respondents reported that they would like to learn more about paediatric palliative care. Over 53% of those surveyed preferred that learning be offered remotely through either internet or correspondence. Seventy-four per cent of respondents expressed they had adequate or very adequate self-care strategies to meet their own needs of well-being.

Conclusions

The results of the survey will guide the paediatric palliative care community to design programmes that will better educate practicing physicians and future physicians about paediatric palliative and end of life care, healthcare services and family communication and support.
Multicentre, double-blind, randomised placebo-controlled clinical trial on the efficacy of methylphenidate on depressive symptoms in advanced cancer patients
Authors: Centeno Carlos , Sanz Alvaro , Cuervo Miguel Angel , Ramos Daniel , Hernansanz Silvia , Gonzalez Jesús , Almaraz Maria Jose , Lama Marcos , Vara Francisco , Nabal María , Pascual Antonio
Published: June 2012

Introduction

Methylphenidate is a psychostimulant that has been used to relieve depressive symptoms in advanced cancer patients. No studies compare its efficacy against placebo in this group of patients.

Objective

To explore the efficacy of methylphenidate compared with placebo in the relief of depressive symptoms in advanced cancer patients.

Material and methods

A multicentre, double-blind, randomised placebo-controlled clinical trial was undertaken comparing the efficacy of methylphenidate and placebo in depressive symptoms. Advanced stage cancer patients were eligible if they scored at least two points on the Two Question Screening Survey for depression. A reduction of at least two points on the Edmonton Symptom Assessment Scale for depression (0–10) was considered as a response.

Results

Sixty-nine patients were included (methylphenidate: n=31, placebo: n=38); median daily dose of methylphenidate was 25 mg. Fifty-eight patients (84%) who completed the first week of treatment were considered suitable for evaluation. In the intention to treat analysis, there were 14/31 (45%) responses with methylphenidate and 10/38 (26%) responses with placebo (difference: 19%; 95% CI: 4% to 39%; p=0.10). With the Hospital Anxiety and Depression Scale, 11/19 (58%) patients with methylphenidate and 10/24 (42%) with placebo improved from a score compatible with depression in the first 7 days (difference 16%; 95% CI 13% to 42%; p=0.29). The proportion of patients indicating adverse effects was similar for both cohorts (p=0.99).

Conclusion

Compared with the placebo, methylphenidate demonstrated a positive trend in the incidence of response for depressive symptoms in advanced cancer patients.
A comparison of cognitive function, sleep and activity levels in disease-free breast cancer patients with or without cancer-related fatigue syndrome
Authors: Minton Ollie , Stone Patrick C
Published: June 2012

Background

Chronic fatigue is a feature in a subset of women successfully treated for breast cancer but is not well characterised. This study examines differences in objective cognitive function, activity levels and sleep in disease-free women who do and do not meet criteria for cancer-related fatigue syndrome (CRFS).

Methods

Women between 3 months and 2 years after completion of any primary therapy were recruited from a cancer centre follow-up clinic. On the basis of a diagnostic semi-structured interview they were classified as being CRFS cases or non-fatigued controls. Participants underwent objective cognitive testing using a computerised battery, wore an activity monitor for 1 week and completed quality of life and fatigue questionnaires.

Results

114 women were recruited (69 controls and 45 CRFS cases). There were significant differences between groups on fatigue, mood, sleep and quality of life scores, and in objective cognitive testing (tests of sustained attention, reaction time and verbal memory all p<0.03). There was an overall difference in daytime activity (p=0.03) from actigraphy recordings. There were no differences on objective measures of sleep or in routine laboratory measures.

Conclusions

Our preliminary results suggest that disease-free women with CRFS after successful breast cancer treatment have significantly lower subjective quality of life and mood. Additionally, objective cognitive impairment in certain domains may play an important role in the subjective manifestation of these symptoms. There is also objective evidence on actigraphy of differing levels of activity. The subjective sleep disturbance and higher prevalence of insomnia do not correlate with objective measures.
Hospice inpatients' views on physical examination by medical students: is it acceptable?
Authors: Hayes Jennifer
Published: June 2012

Objectives

Hospices are increasingly involved in medical student teaching, which the patients generally enjoy. No studies have specifically investigated how hospice patients view the prospect of physical examination by students. Previous evidence involves patients who have already seen students, while the views of other patients are unknown. This study aimed to provide an initial understanding of the views of a diverse group of hospice inpatients on the acceptability and perceived importance of students physically examining them.

Methods

42 hospice inpatients completed a short questionnaire focusing on their views of medical students examining them. Patients chose to do this alone or via a short interview. All inpatients at Exeter Hospice were considered eligible, including patients who were asked and those who may not have been asked to see students; all 42 patients completed the study.

Results

In accordance with existing evidence, patients generally held positive views about seeing students. However, many patients expressed concerns about being physically examined by students, specifically including that it might be painful, tiring or embarrassing. Most importantly, several patients who did not wish to be examined by medical students said they would feel obliged to accept it, or would find it difficult to decline.

Conclusions

Hospice inpatients generally wish to be involved in medical student teaching, but many are concerned about being physically examined, and some feel a sense of obligation to participate. There are implications for hospices that teach students. Further research is necessary to investigate the frequency and severity of these concerns.
On the emotional connection of medical specialists dealing with death and dying: a qualitative study of oncologists, surgeons, intensive care specialists and palliative medicine specialists
Authors: Zambrano Sofia Carolina , Chur-Hansen Anna , Crawford Brian
Published: June 2012

Objectives

This paper reports on qualitative data exploring the experiences and coping mechanisms of medical specialists from the specialties of intensive care, surgery, oncology and palliative care, when dealing with death and dying and their emotional connection with dying patients in the context of a life-threatening illness.

Methods

Thirty-three semi-structured individual interviews were analysed using thematic analysis.

Results

One of the key themes of medical specialists' experiences with death and dying was their ambivalence about developing emotional connections with patients and families. Advantages of not engaging emotionally with patients were related to preserving objectivity in the decision making process, while a perceived disadvantage was the loss of the opportunity to engage in meaningful relationships that could positively influence patients, families and the medical specialist. Finding a balance in the face of ambivalence was a preferred approach and participants employed a variety of coping strategies.

Conclusions

Participants took different positions about the emotional connection that should develop with their dying patients and their families. Although there was agreement about finding a balance between objectivity and connection, their strategies for achieving this seem to be subjective and prescribed by individual notions. By sharing perspectives and learning how other colleagues deal with similar issues, there is an opportunity for medical practitioners to develop a well-rounded approach to dealing with death and dying, which may enhance personal and professional relationships and may ultimately influence future generations of medical practitioners.
Patients' reports or clinicians' assessments: which are better for prognosticating?
Authors: Stone Paddy , Gwilliam Bridget , Keeley Vaughan , Todd Chris , Gittins Matthew , Kelly Laura , Barclay Stephen , Roberts Chris
Published: June 2012

Background

The Prognosis in Palliative care Scale (PiPS) predicts survival in advanced cancer patients more accurately than a doctor's or a nurse's estimate. PiPS scores are derived using observer ratings of symptom severity and performance status. The purpose of this study was to determine whether patient-rated data would provide better prognostic estimates than clinician observer ratings.

Patients and methods

1018 subjects with advanced cancer no longer undergoing tumour-directed therapy were recruited to a multi-centre study. Prognostic models were developed using observer ratings, patient ratings or a composite method that used patient ratings when available or else used observer ratings. The performance of the prognostic models was compared by determining the agreement between the models' predictions and the survival of study participants.

Results

All three approaches to model development resulted in prognostic scores that were able to differentiate between patients with a survival of ‘days’, ‘weeks’ or ‘months+’. However, the observer-rated models were significantly (p<0.05) more accurate than the patient-rated models.

Conclusions

A prognostic model derived using observer-rated data was more accurate at predicting survival than a similar model derived using patient self-report measures. This is clinically important because patient-rated data can be burdensome and difficult to obtain in patients with terminal illnesses.
Defining the palliative care patient: its challenges and implications for service delivery
Authors: Mitchell Helen , Noble Simon , Finlay Ilora , Nelson Annmarie
Published: June 2012

Background

Within the UK, general practitioners (GPs) are required to maintain a register of palliative patients under their care. The term ‘palliative’ when applied to patients encompasses a highly heterogeneous population with varying meanings amongst health professionals. We explored GPs views of what defines a palliative care patient in the context of identifying clinical service needs.

Methods

Audiotaped semi-structured interviews were conducted with GPs to explore how they identify patients requiring inclusion on a palliative care register. Thematic analysis was undertaken and emerging themes identified.

Results

Major themes suggested GPs found it difficult to define the palliative care patient. The decision to include a patient on the palliative care register was made as a multidisciplinary team. Patients not identified as ‘palliative’ were often discussed unofficially if care requirements were significant or prognosis uncertain. The needs of patients with non-malignant disease were considered equal to those with cancer but the challenges of identifying such patients greater. More emphasis was placed on intensity of care required than prognosis. Inclusion on a register triggered greater professional input and was considered beneficial to patient care.

Conclusions

No definition of the palliative care patient exists in working practice and without one there is a risk that some patients with palliative needs will not receive the necessary support, while others may access valuable resources before time. Achieving health policy targets which require identification of palliative patients will continue to be a challenge until a workable and reliable definition of the term ‘palliative’ is agreed upon.
Reduction of gastric inflation by use of a pressure relief valve connected to an acoustic expiration control device during mouth-to-mask ventilation of a manikin model of an unprotected airway
Authors: Mutzbauer Elke Elisabeth , Weiss Manfred , Mutzbauer Till Sebastian
Published: June 2012

Background

Gastric inflation is a significant issue when ventilation of the unprotected airway is performed. The purpose of this study was to evaluate a prototype pressure relief valve with an acoustic expiration control mechanism connected to two different masks.

Methods

12 non-physician healthcare professionals (group 1) and 10 newly certified dentists (group 2) performed 10 cycles of cardiopulmonary resuscitation on a manikin using this device compared with mouth-to-mouth technique. Dentists also employed a mask without the valve. Lower oesophageal sphincter pressures had been adjusted to 1.5 kPa (group 1) and 0.3 kPa (group 2); the valve relief pressure to 1.5 kPa (group 1) and 2.0 kPa (group 2).

Results

In group 1 tidal volumes by valve mask techniques (medians 350 and 400 ml) differed minimally from mouth-to-mouth ventilation (medians 475 and 600 ml). Almost no gastric inflation was observed. Gastric inflation only occurred using the safety valve connected to the mask (median 122 ml) and the mask alone (median 260 ml) (p=0.004). Only in group 1 the acoustic device delivered adequate signals.

Conclusion

Gastric inflation occurred less frequently and to a lesser extent when the valve was connected, going ahead with a trend towards lower tidal volumes. The protective effect of the safety valve may be of benefit even if it leads to smaller tidal volumes.
The impact of 24 h consultant shop floor presence on emergency department performance: a natural experiment
Authors: Christmas Emma , Johnson Ian , Locker Thomas
Published: June 2012

Objectives

As a result of gaps in middle-grade cover in the emergency department it became necessary for consultants to work some night shifts. This study aimed to examine the effect of this change in practice on performance.

Methods

A prospective observational study was conducted. Staffing and workload variables were collected over a period of 6 months in a single district general emergency department. The outcomes assessed were process times, the proportion of patients admitted and the proportion of patients returning within 7 days.

Results

Consultants worked 26 of 182 night shifts during the period studied. There were no differences in the number of patients present in the department at the start of the middle-grade or consultant night shifts. Fewer patients presented per hour during middle-grade night shifts: 3.8 patients per hour versus 4.4 patients per hour during consultant nights. Compared with middle-grade night shifts, the median waiting time was on average 19.6 min less and the median emergency department length of stay was 20.5 min less during consultant night shifts. The proportion of patients admitted from the emergency department was on average 3.9% less than during middle-grade night shifts but there was no difference in the proportion returning within 7 days.

Conclusion

In this small single-site study, a consultant working nights has been shown to reduce process times and the rate of admission. It remains unclear whether such improvements would be sustained in the longer term.
Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease
Authors: Deshpande Vikram , Huck Amelia , Ooi Esther , Stone John H , Faquin William C , Nielsen G Petur
Published: June 2012

Hashimoto thyroiditis (HT) and the fibrosing variant of Hashimoto thyroiditis (FVHT) are immune-mediated tumefactive lesions of the thyroid. Immunoglobulin G4-related disease (IgG4-RD) is now a widely recognised multi-organ system disease characterised by elevated serum and tissue concentrations of IgG4. In this study, the authors address several unresolved questions pertaining to the relationship between HT and FVHT, and the association of each of these diseases with IgG4-RD.

The authors evaluated 28 consecutive cases of HT and nine cases of FVHT. The clinical, demographic and serological data were recorded. The slides were stained immunohistochemically using antibodies to IgG4 and IgG and the quantitative analysis was recorded. Data on thyroid function tests were available on seven cases of FVHT and 14 cases of HT. Based on the availability of data, hypothyroidism was noted in 62% (9/14) of HT and 86% of FVHT (6/7). FVHT demonstrated an exaggerated lobular pattern with lobules separated by cellular storiform-type fibrosis, resembling fibrosis seen in other forms of IgG-RD. The median IgG4 counts per high power field (×40) in HT and FVHT were 2.3 and 22, respectively. The median IgG4:IgG ratios in HT and FVHT were 0.11 and 0.58, respectively. The authors propose that FVHT belongs to the spectrum of IgG4-RD. Although a proportion of cases of HT show elevated numbers of IgG4 positive plasma cells, these cases lack the histological features typically associated with IgG4-RD, and thus the relationship between HT and IgG4-RD remains unproven.
Association of plasma cell subsets in the bone marrow and free light chain concentrations in the serum of monoclonal gammopathy patients
Authors: Ayliffe Michael John , Behrens Judith , Stern Simon , Sumar Nazira
Published: June 2012

This study investigated bone marrow plasma cell subsets and monoclonal free light chain concentrations in blood of monoclonal gammopathy patients. 54 bone marrow samples were stained by double immunofluorescence to enumerate cellular subsets making either intact monoclonal immunoglobulin or free light chains only. Blood taken at the same time was assayed for free light chains by an automated immunoassay. Patients were assigned to three cellular population categories: single intact monoclonal immunoglobulin (59%), dual monoclonal immunoglobulin and free light chain only (31%), or single free light chain only (9%). The median affected free light chain concentration of each group was 75 mg/l, 903 mg/l and 3320 mg/l, respectively, but with substantial overlap. In myeloma patients the difference in serum free light chain concentrations between patients with free light chain only marrow cells and those without was statistically significant. Serum free light chain levels >600 mg/l result mostly from marrow cells restricted to free light chain production.
Assessing user preferences for sexually transmitted infection testing services: a discrete choice experiment
Authors: Miners Alec , Llewellyn Carrie , Pollard Alex , Lagarde Mylene , Richardson Daniel , Cairns John , Fisher Martin , Smith Helen
Published: June 2012

Objective

To assess user preferences for different aspects of sexually transmitted infection (STI) testing services.

Design

A discrete choice experiment.

Setting

14 centres offering tests for STIs in East Sussex, England.

Participants

People testing for STIs.

Main outcome measure

(Adjusted) ORs in relation to preferred service characteristics.

Results

3358 questionnaires were returned; mean age 26 (SD 9.4) years. 70% (2366) were recruited from genitourinary medicine (GUM) clinics. The analysis suggested that the most important characteristics to users were whether ‘staff had specialist STI knowledge’ compared with ‘staff without it’ (OR 2.55; 95% CI 2.47 to 2.63) and whether ‘tests for all STIs’ were offered rather than ‘some’ (OR 2.19; 95% CI 2.12 to 2.25). They remained the most important two service characteristics despite stratifying the analysis by variables such as age and sex. Staff levels of expertise were viewed as particularly important by people attending CASH centres, women and non-men who have sex with men. A ‘text or call to a mobile phone’ and ‘dropping in and waiting’ were generally the preferred methods of results reporting and appointment system, respectively.

Conclusions

This study suggests that people testing for STIs place particular importance on testing for all infections rather than some and staff with specialist STI knowledge. Thus, targets based purely on waiting up to 48 h for an appointment are misguided from a user perspective.
Clinical value of blood glucose measurement in pet rabbits
Authors: Harcourt‐Brown F. M. , Harcourt‐Brown S.F.
Published: June 2012

Blood glucose was measured with a portable glucose meter in 907 rabbits, including 238 clinically healthy ones. Blood glucose concentrations ranged from 1.2 to 30.1 mmol/l. Diabetes mellitus was not encountered. No significant effect of sex or sedation was found. Hypoglycaemia was seen in 16 rabbits including one with an insulinoma. There was a significant relationship between blood glucose, food intake, signs of stress and severity of clinical disease. Rabbits showing signs of stress had higher blood glucose than rabbits with no signs and rabbits that were totally anorexic had higher blood glucose values than those that were eating normally or those with reduced food intake. Severe hyperglycaemia (>20 mmol/l) was associated with conditions with a poor prognosis. Rabbits with confirmed intestinal obstruction had a mean blood glucose of 24.7 mmol/l (n = 18). This was significantly higher than the rabbits with confirmed gut stasis, which had a mean value of 8.5 mmol/l (n = 51). The conclusion of the study was that blood glucose is a measurable parameter that can be used to assess the severity of a rabbit's condition and help to differentiate between gut stasis and intestinal obstruction in rabbits that are anorexic.
Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats
Authors: Guimaraes Priscila S. , Santiago Nivia M. , Xavier Carlos H. , Velloso Elizabeth P. P. , Fontes Marco A. P. , Santos Robson A. S. , Campagnole-Santos Maria Jose
Published: June 2012

Angiotensin-(ANG)-(1-7) is known by its central and peripheral actions, which mainly oppose the deleterious effects induced by accumulation of ANG II during pathophysiological conditions. In the present study we evaluated whether a chronic increase in ANG-(1-7) levels in the brain would modify the progression of hypertension. After DOCA-salt hypertension was induced for seven days, Sprague-Dawley rats were subjected to 14 days of intracerebroventricular (ICV) infusion of ANG-(1-7) (200 ng/h, DOCA-A7) or 0.9% sterile saline. As expected, on the 21st day, DOCA rats presented increased mean arterial pressure (MAP) (≈40%), and impaired baroreflex control of heart rate (HR) and baroreflex renal sympathetic nerve activity (RSNA) in comparison with that in normotensive control rats (CTL). These changes were followed by an overactivity of the cardiac sympathetic tone and reduction of the cardiac parasympathetic tone, and exaggerated mRNA expression of collagen type I (≈9-fold) in the left ventricle. In contrast, DOCA rats treated with ANG-(1-7) ICV had an improvement of baroreflex control of HR, which was even higher than that in CTL, and a restoration of the baroreflex control of RSNA, the balance of cardiac autonomic tone, and normalized mRNA expression of collagen type I in the left ventricle. Furthermore, DOCA-A7 had MAP lowered significantly. These effects were not accompanied by significant circulating or cardiac changes in angiotensin levels. Taken together, our data show that chronic increase in ANG-(1-7) in the brain attenuates the development of DOCA-salt hypertension, highlighting the importance of this peptide in the brain for the treatment of cardiovascular diseases.
Effect of healthy aging on left ventricular relaxation and diastolic suction
Authors: Carrick-Ranson Graeme , Hastings Jeffrey L. , Bhella Paul S. , Shibata Shigeki , Fujimoto Naoki , Palmer M. Dean , Boyd Kara , Levine Benjamin D.
Published: June 2012

Doppler ultrasound measures of left ventricular (LV) active relaxation and diastolic suction are slowed with healthy aging. It is unclear to what extent these changes are related to alterations in intrinsic LV properties and/or cardiovascular loading conditions. Seventy carefully screened individuals (38 female, 32 male) aged 21–77 were recruited into four age groups (young: <35; early middle age: 35–49; late middle age: 50–64 and seniors: ≥65 yr). Pulmonary capillary wedge pressure (PCWP), stroke volume, LV end-diastolic volume, and Doppler measures of LV diastolic filling were collected at multiple loading conditions, including supine baseline, lower body negative pressure to reduce LV filling, and saline infusion to increase LV filling. LV mass, supine PCWP, and heart rate were not affected significantly by aging. Measures of LV relaxation, including isovolumic relaxation time and the time constant of isovolumic pressure decay increased progressively, whereas peak early mitral annular longitudinal velocity decreased with advancing age ( P < 0.001). The propagation velocity of early mitral inflow, a noninvasive measure of LV suction, decreased with aging with the greatest reduction in seniors ( P < 0.001). Age-related differences in LV relaxation and diastolic suction were not attenuated significantly when PCWP was increased in older subjects or reduced in the younger subjects. There is an early slowing of LV relaxation and diastolic suction beginning in early middle age, with the greatest reduction observed in seniors. Because age-related differences in LV dynamic diastolic filling parameters were not diminished significantly with significant changes in LV loading conditions, a decline in ventricular relaxation is likely responsible for the alterations in LV diastolic filling with senescence.
Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure
Authors: Deo Shekhar H. , Fisher James P. , Vianna Lauro C. , Kim Areum , Chockalingam Anand , Zimmerman Matthew C. , Zucker Irving H. , Fadel Paul J.
Published: June 2012

Despite standard drug therapy, sympathetic nerve activity (SNA) remains high in heart failure (HF) patients making the sympathetic nervous system a primary drug target in the treatment of HF. Studies in rabbits with pacing-induced HF have demonstrated that statins reduce resting SNA, in part, due to reductions in reactive oxygen species (ROS). Whether these findings can be extended to the clinical setting of human HF remains unclear. We first performed a study in seven statin-naïve HF patients (56 ± 2 yr; ejection fraction: 31 ± 4%) to determine if 1 mo of simvastatin (40 mg/day) reduces muscle SNA (MSNA). Next, to control for possible placebo effects and determine the effect of simvastatin on ROS, a double-blinded, placebo-controlled crossover design study was performed in six additional HF patients (51 ± 3 yr; ejection fraction: 22 ± 4%), and MSNA, ROS, and superoxide were measured. We tested the hypothesis that statin therapy decreases resting MSNA in HF patients and this would be associated with reductions in ROS. In study 1, simvastatin reduced resting MSNA (75 ± 5 baseline vs. 65 ± 5 statin bursts/100 heartbeats; P < 0.05). Likewise, in study 2, simvastatin also decreased resting MSNA (59 ± 5 placebo vs. 45 ± 6 statin bursts/100 heartbeats; P < 0.05). In addition, statin therapy significantly reduced total ROS and superoxide. As expected, cholesterol was reduced after simvastatin. Collectively, these findings indicate that short-term statin therapy concomitantly reduces resting MSNA and total ROS and superoxide in HF patients. Thus, in addition to lowering cholesterol, statins may also be beneficial in reducing sympathetic overactivity and oxidative stress in HF patients.
Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load
Authors: Nivala Michael , Qu Zhilin
Published: June 2012

Intracellular calcium (Ca) alternans in cardiac myocytes have been shown in many experimental studies, and the mechanisms remain incompletely understood. We recently developed a “3R theory” that links Ca sparks to whole cell Ca alternans through three critical properties: randomness of Ca sparks; recruitment of a Ca spark by neighboring Ca sparks; and refractoriness of Ca release units. In this study, we used computer simulation of a physiologically detailed mathematical model of a ventricular myocyte couplon network to study how sarcoplasmic reticulum (SR) Ca load and other physiological parameters, such as ryanodine receptor sensitivity, SR uptake rate, Na-Ca exchange strength, and Ca buffer levels affect Ca alternans in the context of 3R theory. We developed a method to calculate the parameters used in the 3R theory (i.e., the primary spark rate and the recruitment rate) from the physiologically detailed Ca cycling model and paced the model periodically to elicit Ca alternans. We show that alternans only occurs for an intermediate range of the SR Ca load, and the underlying mechanism can be explained via its effects on the 3Rs. Furthermore, we show that altering the physiological parameters not only directly changes the 3Rs but also alters the SR Ca load, having an indirect effect on the 3Rs as well. Therefore, our present study links the SR Ca load and other physiological parameters to whole cell Ca alternans through the framework of the 3R theory, providing a general mechanistic understanding of Ca alternans in ventricular myocytes.
Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion
Authors: Abdillahi Mariane , Ananthakrishnan Radha , Vedantham Srinivasan , Shang Linshan , Zhu Zhengbin , Rosario Rosa , Zirpoli Hylde , Bohren Kurt M. , Gabbay Kenneth H. , Ramasamy Ravichandran
Published: June 2012

Earlier studies have demonstrated that aldose reductase (AR) plays a key role in mediating ischemia-reperfusion (I/R) injury. Our objective was to investigate if AR mediates I/R injury by influencing phosphorylation of glycogen synthase kinase-3β (p-GSK3β). To investigate this issue, we used three separate models to study the effects of stress injury on the heart. Hearts isolated from wild-type (WT), human expressing AR transgenic (ARTg), and AR knockout (ARKO) mice were perfused with/without GSK3β inhibitors (SB-216763 and LiCl) and subjected to I/R. Ad-human AR (Ad-hAR)-expressing HL-1 cardiac cells were exposed to hypoxia (0.5% O2) and reoxygenation (20.9% O2) conditions. I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD) was used to study if p-GSK3β was affected through increased AR flux. Lactate dehydrogenase (LDH) release and left ventricular developed pressure (LVDP) were measured. LVDP was decreased in hearts from ARTg mice compared with WT and ARKO after I/R, whereas LDH release and apoptotic markers were increased ( P < 0.05). p-GSK3β was decreased in ARTg hearts compared with WT and ARKO ( P < 0.05). In ARKO, p-GSK3β and apoptotic markers were decreased compared with WT ( P < 0.05). WT and ARTg hearts perfused with GSK3β inhibitors improved p-GSK3β expression and LVDP and exhibited decreased LDH release, apoptosis, and mitochondrial pore opening ( P < 0.05). Ad-hAR-expressing HL-1 cardiac cells, exposed to hypoxia (0.5% O2) and reoxygenation (20.9% O2), had greater LDH release compared with control HL-1 cells ( P < 0.05). p-GSK3β was decreased and correlated with increased apoptotic markers in Ad-hAR HL-1 cells ( P < 0.05). Treatment with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor increased injury demonstrated by increased LDH release in ARTg, WT, and ARKO hearts and in Ad-hAR-expressing HL-1 cells. Cells treated with protein kinase C (PKC) α/β inhibitor displayed significant increases in p-Akt and p-GSK3β expression, and resulted in decreased LDH release. In summary, AR mediates changes in p-GSK3β, in part, via PKCα/β and Akt during I/R.
Epigenetic upregulation of p66shc mediates low-density lipoprotein cholesterol-induced endothelial cell dysfunction
Authors: Kim Young-Rae , Kim Cuk-Seong , Naqvi Asma , Kumar Ajay , Kumar Santosh , Hoffman Timothy A. , Irani Kaikobad
Published: June 2012

Hypercholesterolemia characterized by elevation of low-density lipoprotein (LDL) cholesterol is a major risk factor for atherosclerotic vascular disease. p66shc mediates hypercholesterolemia-induced endothelial dysfunction and atheromatous plaque formation. We asked if LDL upregulates endothelial p66shc via changes in the epigenome and examined the role of p66shc in LDL-stimulated endothelial cell dysfunction. Human LDL stimulates human p66shc promoter activity and p66shc expression in human endothelial cells. LDL leads to hypomethylation of two CpG dinucleotides and acetylation of histone 3 in the human p66shc promoter. These two CpG dinucleotides mediate LDL-stimulated p66shc promoter activity. Inhibition or knock down of DNA methyltransferases negates LDL-induced endothelial p66shc expression. p66shc mediates LDL-stimulated increase in expression of endothelial intercellular adhesion molecule-1 (ICAM1) and decrease in expression of thrombomodulin (TM). Mirroring these changes in ICAM1 and TM expression, p66shc mediates LDL-stimulated adhesion of monocytes to endothelial cells and plasma coagulation on endothelial cells. These findings indicate that LDL cholesterol upregulates human endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter. Moreover, they show that LDL-stimulated p66shc expression mediates a dysfunctional endothelial cell surface, with proadhesive and procoagulant features.
NAD(P)H quinone oxidoreductase 1 regulates neutrophil elastase-induced mucous cell metaplasia
Authors: Meyer Marisa L. , Potts-Kant Erin N. , Ghio Andrew J. , Fischer Bernard M. , Foster W. Michael , Voynow Judith A.
Published: June 2012

Mucous cell metaplasia (MCM) and neutrophil-predominant airway inflammation are pathological features of chronic inflammatory airway diseases. A signature feature of MCM is increased expression of a major respiratory tract mucin, MUC5AC. Neutrophil elastase (NE) upregulates MUC5AC in primary airway epithelial cells by generating reactive oxygen species, and this response is due in part to upregulation of NADPH quinone oxidoreductase 1 (NQO1) activity. Delivery of NE directly to the airway triggers inflammation and MCM and increases synthesis and secretion of MUC5AC protein from airway epithelial cells. We hypothesized that NE-induced MCM is mediated in vivo by NQO1. Male wild-type and Nqo1-null mice (C57BL/6 background) were exposed to human NE (50 μg) or vehicle via oropharyngeal aspiration on days 1, 4, and 7. On days 8 and 11, lung tissues and bronchoalveolar lavage (BAL) samples were obtained and evaluated for MCM, inflammation, and oxidative stress. MCM, inflammation, and production of specific cytokines, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-2, interleukin-4, and interleukin-5 were diminished in NE-treated Nqo1-null mice compared with NE-treated wild-type mice. However, in contrast to the role of NQO1 in vitro, we demonstrate that NE-treated Nqo1-null mice had greater levels of BAL and lung tissue lipid carbonyls and greater BAL iron on day 11, all consistent with increased oxidative stress. NQO1 is required for NE-induced inflammation and MCM. This model system demonstrates that NE-induced MCM directly correlates with inflammation, but not with oxidative stress.
Angiotensin II regulates activation of Bim via Rb/E2F1 during apoptosis: involvement of interaction between AMPKβ1/2 and Cdk4
Authors: Kim Yong-Chul , Day Regina M.
Published: June 2012

Apoptotic cell death is essential for mammalian development and tissue homeostasis. Dysregulation of apoptosis has been identified in pathologies including in pulmonary fibrotic remodeling. We previously reported that a key proapoptotic factor in fibrosis, angiotensin II (Ang II), mediates apoptosis in primary pulmonary artery endothelial cells (PAEC) via the AT2 receptor and requires activation of AMP-regulated protein kinase (AMPK). We now demonstrate that Ang II induces E2F1 transcription factor binding to and activation of the promoter for the Bcl-2 homology 3 (BH3)-only protein Bim. In PAEC, Ang II treatment induced cyclin-dependent kinase 4 (Cdk4)-mediated hyperphosphorylation of retinoblastoma protein (Rb) and its disassociation from E2F1, a key step in facilitating E2F1-directed transcriptional activity. Indeed, ectopic expression of a dominant negative Cdk4 mutant inhibited Ang II-mediated hyperphosphorylation of Rb and Bim promoter activation. Our data also show that the β-subunit of AMPK was constitutively associated with Cdk4 in PAEC and that Ang II treatment induced AMPKβ phosphorylation and subsequent disassociation of this complex. Both Ang II-induced Rb hyperphosphorylation and Cdk4-AMPK disassociation were blocked by the AMPK inhibitor compound C. Together these findings illuminate a novel proapoptotic signaling pathway in endothelial cells, whereby Ang II triggers E2F1-mediated transcriptional upregulation of Bim via activation of AMPKβ1/2 and Cdk4.
Improved throughput traction microscopy reveals pivotal role for matrix stiffness in fibroblast contractility and TGF-β responsiveness
Authors: Marinković Aleksandar , Mih Justin D. , Park Jin-Ah , Liu Fei , Tschumperlin Daniel J.
Published: June 2012

Lung fibroblast functions such as matrix remodeling and activation of latent transforming growth factor-β1 (TGF-β1) are associated with expression of the myofibroblast phenotype and are directly linked to fibroblast capacity to generate force and deform the extracellular matrix. However, the study of fibroblast force-generating capacities through methods such as traction force microscopy is hindered by low throughput and time-consuming procedures. In this study, we improved at the detail level methods for higher-throughput traction measurements on polyacrylamide hydrogels using gel-surface-bound fluorescent beads to permit autofocusing and automated displacement mapping, and transduction of fibroblasts with a fluorescent label to streamline cell boundary identification. Together these advances substantially improve the throughput of traction microscopy and allow us to efficiently compute the forces exerted by lung fibroblasts on substrates spanning the stiffness range present in normal and fibrotic lung tissue. Our results reveal that lung fibroblasts dramatically alter the forces they transmit to the extracellular matrix as its stiffness changes, with very low forces generated on matrices as compliant as normal lung tissue. Moreover, exogenous TGF-β1 selectively accentuates tractions on stiff matrices, mimicking fibrotic lung, but not on physiological stiffness matrices, despite equivalent changes in Smad2/3 activation. Taken together, these results demonstrate a pivotal role for matrix mechanical properties in regulating baseline and TGF-β1-stimulated contraction of lung fibroblasts and suggest that stiff fibrotic lung tissue may promote myofibroblast activation through contractility-driven events, whereas normal lung tissue compliance may protect against such feedback amplification of fibroblast activation.
Coincidence Points for Expansive Mappings underc-Distance in Cone Metric Spaces
Authors: Aydi Hassen , Karapınar Erdal , Moradi Sirous
Published: June 2012

We establish some fixed (common fixed) and coincidence point results for mappings verifying some expansive type contractions in cone metric spaces with the help of the concept of ac-distance. Our results generalize, extend, and unify several well-known comparable results in the literature. Some examples are also presented.
Macrolide Therapy in Respiratory Viral Infections
Authors: Min Jin-Young , Jang Yong Ju
Published: June 2012

Background. Macrolides have received considerable attention for their anti-inflammatory and immunomodulatory actions beyond the antibacterial effect. These two properties may ensure some efficacy in a wide spectrum of respiratory viral infections. We aimed to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection.Methods. A search of electronic journal articles through PubMed was performed using combinations of the following keywords including macrolides and respiratory viral infection.Results. Bothin vitroandin vivostudies have provided evidence of their efficacy in respiratory viral infections including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus. Much data showed that macrolides reduced viral titers of RV ICAM-1, which is the receptor for RV, and RV infection-induced cytokines including IL-1β, IL-6, IL-8, and TNF-α. Macrolides also reduced the release of proinflammatory cytokines which were induced by RSV infection, viral titers, RNA of RSV replication, and the susceptibility to RSV infection partly through the reduced expression of activated RhoA which is an RSV receptor. Similar effects of macrolides on the influenza virus infection and augmentation of the IL-12 by macrolides which is essential in reducing virus yield were revealed.Conclusion. This paper provides an overview on the properties of macrolides and their efficacy in various respiratory diseases.
Study Bioprospecting of Medicinal Plant Extracts of the Semiarid Northeast: Contribution to the Control of Oral Microorganisms
Authors: Silva Maria Suênia P. , Brandão Deysiane O. , Chaves Thiago P. , Formiga Filho Amaro L. N. , Costa Edja Maria M. de B. , Santos Vanda L. , Medeiros Ana Cláudia D.
Published: June 2012

Dental pathologies can be caused by plaque-forming bacteria and yeast, which reside in the oral cavity. The bacteria growing in dental plaque, a naturally occurring biofilm, display increased resistance to antimicrobial agents. The objective was the evaluation of a preclinical assay of medicinal plants of the semiarid region from the northeast against oral pathogenic microorganism, aiming at bioprospecting a new product. The selection of plant material for this study was based on the ethnobotanical data on the traditional use of plants from the semiarid region. The thirty extracts were subjected to the determination of antibiofilm activity against gram-positive, gram-negative bacteria and yeast. The hydroalcoholic extract which showed positive antibiofilm activity against most of the microorganisms tested in agar diffusion assay was further tested for the determination of minimum inhibitory concentration (MIC) and Bioassay withArtemia salina. Plant samples tested in this study exhibited good antibiofilm activity for the treatment of oral problems. TheSchinopsis brasiliensisshowed greater activity forPseudomonas aeruginosaandStaphylococcus aureus, but toxicity againstArtemia salina.
A Pilot Study for the Neuroprotective Effect of Gongjin-dan on Transient Middle Cerebral Artery Occlusion-Induced Ischemic Rat Brain
Authors: Sunwoo Yun-Young , Park Sang In , Chung Yong-An , Lee Jisoo , Park Moon-Seo , Jang Kyung-Sool , Maeng Lee-So , Jang Dong-Kyu , Im Ruth , Jung Yu Jin , Park Soon A. , Kang Eun-Sun , Kim Min-Wook , Han Young-Min
Published: June 2012

In this study, we investigated whether gongjin-dan improves functional recovery and has neuroprotective effects on reducing the infarct volume after transient middle cerebral artery occlusion (MCAo). Infarct volume was measured using TTC staining and glucose utilization by F-18 FDG PET. Functional improvement was evaluated with the Rota-rod, treadmill, Garcia score test, and adhesive removal test. At 14 days after MCAo, neuronal cell survival, astrocytes expansion, and apoptosis were assessed by immunohistofluorescence staining in the peri-infarct region. Also, the expression of neurotrophic factors and inflammatory cytokines such as VEGF, BDNF, Cox-2, TNF-α, IL-1β, and IL-1αwas measured in ischemic hemisphere regions. The gongjin-dan-treated group showed both reduced infarct volume and increased glucose utilization. Behavior tests demonstrated a significant improvement compared to the control. Also in the gongjin-dan treated group, NeuN-positive cells were increased and number of astrocytes, microglia, and apoptotic cells was significantly decreased compared with the control group in the ischemic peri-infarct area. Furthermore, the expression of VEGF and BDNF was increased and level of Cox-2, TNF-α, IL-1β, and IL-1αwas decreased. These results suggest that gongjin-dan may improve functional outcome through the rapid restoration of metabolism and can be considered as a potential neuroprotective agent.