No Evidence That Frontal Eye Field tDCS Affects Latency or Accuracy of Prosaccades.
Transcranial direct current stimulation (tDCS) may be used to directly affect neural activity from outside of the skull. However, its exact physiological mechanisms remain elusive, particularly when applied to new brain areas. The frontal eye field (FEF) has rarely been targeted with tDCS, even though it plays a crucial role in control of overt and covert spatial attention. Here, we investigate whether tDCS over the FEF can affect the latency and accuracy of saccadic eye movements. Twenty-six participants performed a prosaccade task in which they made eye movements to a sudden-onset eccentric visual target (lateral saccades). After each lateral saccade, they made an eye movement back to the center (center saccades). The task was administered before, during, and after anodal or cathodal tDCS over the FEF, in a randomized, double-blind, within-subject design. One previous study (Kanai et al., 2012) found that anodal tDCS over the FEF decreased the latency of saccades contralateral to the stimulated hemisphere. We did not find the same effect: neither anodal nor cathodal tDCS influenced the latency of lateral saccades. tDCS also did not affect accuracy of lateral saccades (saccade endpoint deviation and saccade endpoint variability). For center saccades, we found some differences between the anodal and cathodal sessions, but these were not consistent across analyses (latency, endpoint variability), or were already present before tDCS onset (endpoint deviation). We tried to improve on the design of Kanai et al. (2012) in several ways, including the tDCS duration and electrode montage, which could explain the discrepant results. Our findings add to a growing number of null results, which have sparked concerns that tDCS outcomes are highly variable. Future studies should aim to establish the boundary conditions for FEF-tDCS to be effective, in addition to increasing sample size and adding additional controls such as a sham condition. At present, we conclude that it is unclear whether eye movements or other aspects of spatial attention can be affected through tDCS of the frontal eye fields.


Synaptic organization of dorsal root projections to lumbar motoneurons in the clawed toad (Xenopus laevis).
Synaptic connexions between dorsal root primary afferents and lumbar motoneurons have been investigated in the isolated spinal cord of the clawed toad. The study of monosynaptic actions evoked in motoneurons by 9th or 10th dorsal root stimulation or by impulses in single primary afferents provided evidence for both electrical and chemical junctional transmission at the sensory-motor synapses. The anterograde filling of the 9th and 10th dorsal roots with horseradish peroxidase (HRP) shows that afferents do project to the motoneuron field of the segments IX and X. Some of the fibres not only reach the dorsally located motoneurons, but also cross the lateral motor column (LMC) and terminate in the marginal zone of ventral horn gray matter. The projections of the 9th and 10th dorsal root fibres are most numerous in the caudal part of segment X. Simultaneous HRP labeling of single motoneurons and the whole 10th dorsal root has revealed that afferent fibres make contacts not only on the distal dendrites of the motor cells, but also on the proximal ones. This latter finding is in a good agreement with the electrophysiological data.


Two new species of Lasiopa (Diptera, Stratiomyidae) from Turkey.
Two new species, Lasiopa aksarayiensis sp. n. and Lasiopa aktasii sp. n. are described from the Central Anatolian stepe in Turkey. All diagnostic characters are illustrated and possible relationships of both taxa are briefly discussed. The first record of Lasiopa pseudovillosa (Rozkošný, 1983) from Turkey is presented and additional Turkish localities of Lasiopa caucasica (Pleske, 1901) are recorded and an identification key to all the Palaearctic species of Lasiopa is given.


Recommendations to support deprescribing medications late in life.
It is widely acknowledged that patients-particularly those late in life-are frequently exposed to the harms of medication. To minimize these harms, several frameworks have been developed by which prescribing can be optimized. In the context of diminishing life expectancy, these frameworks can be used to reduce medications that are no longer necessary, but appear to fall short of actual guidelines that incorporate a consideration of stopping medications. In this commentary, we present recommendations that could be incorporated into prescribing processes for all healthcare professionals and, ultimately, used to support the rationalization or deprescribing of medication in diminished life expectancy. We frame these recommendations in the same context as guidance for the initiation and discontinuation of implantable cardiac devices and argue that the two processes-with regards to decision-making-should be the same. We present our recommendations with preventive medication use in mind, and use statin therapy as an illustrative example.


Effect of fundholding and indicative prescribing schemes on general practitioners' prescribing costs.
To compare general practitioners' prescribing costs in fundholding and non-fundholding practices before and after implementation of the NHS reforms in April 1991. Analysis of prescribing and cost information (PACT data; levels 2 and 3) over two six month periods in 1991 and 1992. Oxford region. Three dispensing fundholding practices; five non-dispensing fundholding practices; and seven non-dispensing, non-fundholding practices. Percentage change in net cost of ingredients, number of items prescribed, average cost per item, and proportion of generic drugs prescribed after NHS reforms. Prescribing costs increased in all practices in the six months after the reforms. The net costs of ingredients increased among dispensing fundholders by 10.2%, among non-dispensing fundholders by 13.2%, and among non-fundholders by 18.7%. The number of items prescribed also increased in all three groups (by 5.2%, 7.5%, and 6.1% respectively). The increase in average cost per item was 4.8% for dispensing fundholders, 5.3% for non-dispensing fundholders, and 11.9% for non-fundholders. Dispensing fundholders increased the proportion of generic drugs prescribed from 26.9% to 34.5% and non-dispensing fundholders from 44.5% to 48.7%; non-fundholders showed no change (47%). Five of the eight fundholding practices made savings in their drugs budgets at the end of the first year of fundholding (range 2.9-10.7%; the three other practices overspent by up to 3.6%). All non-fundholding practices exceeded their indicative prescribing amounts (range 3.2-20.0%). Fundholding has helped to curb increases in prescribing costs, even among dispensing general practitioners, for whom the incentives are different. Indicative prescribing amounts for non-fundholding practices do not seem to have had the same effect.


Disopyramide use in infants and children with hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy has a range of clinical severity in children. Treatment options are limited, mainly on account of small patient size. Disopyramide is a sodium channel blocker with negative inotropic properties that effectively reduces left ventricular outflow tract gradients in adults with hypertrophic cardiomyopathy, but its efficacy in children is uncertain. A retrospective chart review of patients ⩽21 years of age with hypertrophic cardiomyopathy at our institution and treated with disopyramide was performed. Left ventricular outflow tract Doppler gradients before and after disopyramide initiation were compared as the primary outcome measure. Nine patients received disopyramide, with a median age of 5.6 years (range 6 days-12.9 years). The median left ventricular outflow tract Doppler gradient before initiation of disopyramide was 81 mmHg (range 30-132 mmHg); eight patients had post-initiation echocardiograms, in which the median lowest recorded Doppler gradient was 43 mmHg (range 15-100 mmHg), for a median % reduction of 58.2% (p=0.002). With median follow-up of 2.5 years, eight of nine patients were still alive, although disopyramide had been discontinued in six of the nine patients. Reasons for discontinuation included septal myomectomy (four patients), heart transplantation (one patient), and side effects (one patient). Disopyramide was effective for the relief of left ventricular outflow tract obstruction in children with hypertrophic cardiomyopathy, although longer-term data suggest that its efficacy is not sustained. In general, it was well tolerated. Further study in larger patient populations is warranted.


Using of modified rapid palate expander with miniscrews in a patient affected by ectodermic dysplasia.
To show the orthodontic treatment in a 8-year-old patient affected by Ectodermal Dysplasia (hypohidrotic type) and presenting multiple agenesiae, contraction of the maxilla and skeletal Class III malocclusion. Because of both oligodontia of primary and secondary dentition and no good retention and anchoring, a hybrid modified rapid palatal expander (RPE) was used. It presented dental anchoring with two bands on first upper molars and skeletal anchoring with two miniscrews in the anterior palate. The project included the use of a CBTC for the bone examination and precise silicon dental impression for the insertion of miniscrews. The procedure was successful and the patient solved the expansion in few days, so RPE has been embedded throughout 6 months in order to develop the bone at the median suture. This case report can be considered as a valid example for approaching patients affected by Ectodermal Dysplasia with multiple agenesiae and palatal contraction because of the difficult retention.


Differential profile of ultrasound findings associated with malignancy in mixed and solid thyroid nodules in an elderly female population.
Objective. Ultrasonographic characteristics are associated with thyroid malignancy. Our aim was to compare the diagnostic value of ultrasound features in the detection of thyroid malignancy in both solid and mixed nodules. Methods. We prospectively studied female patients (≥50 years) referred to ultrasound-guided fine needle aspiration biopsy. Ultrasound features considered suspicious were hypoechogenicity, microcalcifications, irregular margins, high anteroposterior (AP)/axial-ratio, and absent halo. Associations were separately assessed in mixed and solid nodules. Results. In a group of 504 elderly female patients (age = 69 ± 8 years), the frequency of malignant cytology was 6%. Thirty-one percent of nodules were mixed and 60% were solid. The rate of malignant cytology was similar for mixed and solid nodules (7.4 versus 5.8%, P: 0.56). While in mixed nodules none of the ultrasound characteristics were associated with malignant cytology, in solid nodules irregular margins and microcalcifications were significant (all P < 0.05). The combination of irregular margins and/or microcalcifications significantly increased the association with malignant cytology only in solid nodules (OR: 2.76 (95% CI: 1.25-6.10), P: 0.012). Conclusions. Ultrasound features were of poor diagnostic value in mixed nodules, which harbored malignant lesions as often as solid nodules. Our findings challenge the recommended minimal size for ultrasound-guided fine needle aspiration biopsy in mixed nodules.


Proximal humeral fractures: a systematic review of treatment modalities.
A systematic review was conducted of primary intervention of proximal humeral fracture, which is a common injury with significant morbidity. Keywords of proximal humeral fracture were entered into PubMed and Embase databases. Two evaluators reviewed abstracts from 1985 to 2004 for inclusion and exclusion criteria yielding 66 articles. These articles were evaluated independently for outcomes and quality of evidence using the Structured Effectiveness Quality Evaluation Scale and Sackett's Levels of Evidence. Patient characteristics and outcomes were recorded. The 66 studies included 2155 patients grouped by fracture types according to the Neer classification system. Studies differed by intervention, methods, outcome measures and results. Quality scores averaged 15/48; only 2 articles included randomized groups. Current studies typically lack randomization, comparators, and independent evaluation, with a resultant inability to produce clinical conclusions. Further research comparing primary treatment methods in a properly designed and controlled fashion is required, ideally using randomized controlled trials.


Canonical and noncanonical Wnt pathways: a comparison between endometrial cancer type I and atrophic endometrium in Brazil.
The Wnt pathway is involved in tumorigenesis of several tissues. For this reason, we proposed to evaluate Wnt gene expression in endometrial cancer type I. Cross-sectional study on materials gathered from the tissue bank of the Department of Pathology, Universidade Federal de São Paulo. Endometrial specimens were obtained from surgeries performed between 1995 and 2005 at São Paulo Hospital, Universidade Federal de São Paulo. The material was divided into two groups according to tissue type: Group A, atrophic endometrium (n = 15); and Group B, endometrial adenocarcinoma (n = 45). We compared the immunohistochemical expression of Wnt1, Frizzled-1 (FZD1), Wnt5a, Frizzled-5 (FZD5) and beta-catenin between endometrial cancer type I and atrophic endometrium. Regarding Wnt1, FZD1 and Wnt5a expression, no significant association was observed between the groups. A significant association was observed between the groups in relation to FZD5 expression (P = 0.001). The proportion of FZD5-positive samples was significantly higher in group A (80.0%) than in group B (31.1%). Regarding the survival curve for FZD5 in group B, we did not find any significant association between atrophic endometrium and endometrial adenocarcinoma. We also did not find any significant association regarding beta-catenin expression (P = 1.000). FZD5 is downregulated in endometrial adenocarcinoma, in comparison with atrophic endometrium.


Adapting an Evidence-Based Intervention Targeting HIV-Infected Prisoners in Malaysia.
HIV-infected prisoners in Malaysia represent a critical target population for secondary HIV risk reduction interventions and care. We report on the process and outcome of our formative research aimed at systematically selecting and adapting an EBI designed to reduce secondary HIV risk and improve adherence to antiretroviral therapy among soon-to-be-released HIV-infected prisoners. Our formative work involved a critical examination of established EBIs and associated published reports complemented by data elicited through structured interviews and focus groups with key stakeholders, members of the target population, and their family members. Based on all information, we adapted the Holistic Health Recovery Program targeting people living with HIV (HHRP+), an EBI, to consist of eight 2-hour sessions that cover a range of specified topics so that participants may individually apply intervention content as needed to accommodate their particular substance abuse, HIV risk, and antiretroviral adherence issues. This study provides a complete example of the process of selecting and adapting an EBI-taking into account both empirical evidence and input from target organization stakeholders and target population members and their families-for use in real world prison settings where high-risk populations are concentrated.


Medical cost of environmental pollution: evidence from the Chinese Social Survey.
Environmental pollution impairs residents' health, while the pursuit of health is highly correlated to medical costs. Understanding how environmental pollution affects medical costs is closely linked to the welfare of society. Based on theoretical analysis, this paper uses data from 5112 households of the Chinese Social Survey (CSS) in 2019, constructs a composite indicator to quantify environmental pollution using respondents' evaluations, and empirically investigates the causal effect of environmental pollution on household medical cost and the mechanism. The conclusions are shown as follows. First, environmental pollution can increase household medical costs, and this estimation result still holds after dealing with the endogeneity problem and other robustness tests. Second, there is heterogeneity in the impact of environmental pollution on household medical costs, households in the upper socioeconomic class, with heavy pension burdens or with strong health insurance coverage are more sensitive to environmental pollution and incur relatively higher household medical costs. Third, environmental pollution reduces residents' satisfaction with their spiritual life, which adversely affects their physical and mental health and can increase household medical costs. Residents' satisfaction with their spiritual life is an important mechanism for environmental pollution to affect household health care expenditures. Therefore, governments should enhance the enforcement of environmental protection and governance, strengthen the awareness of green issues and health education, and increase the supply of facilities for leisure and sports, thus reducing medical costs due to environmental pollution and easing the medical burden of residents.


Antineoplastic activity of a series of boron analogues of alpha-amino acids.
A series of amine cyanoboranes, amine carboxyboranes, and boron analogues of alpha-amino acids have been investigated for antineoplastic activity against the growth of Ehrlich ascites cells. Additional studies demonstrated that the boron analogues inhibited DNA and RNA synthesis at 300 microM. The suppression of DNA synthesis of Ehrlich ascites cells correlated with the reduction of DNA polymerase, 5-phosphoribosyl-1-pyrophosphate amidotransferase, and dihydrofolate reductase activities afforded by the boron compounds. These derivatives did not suppress protein synthesis, thymidylate synthetase, or thymidine monophosphate kinase activities as previously reported for some boron antineoplastic agents.


Charge Injection, Carriers Recombination and HOMO Energy Level Relationship in Perovskite Solar Cells.
We present a comparative study between a series of well-known semiconductor polymers, used in efficient organic solar cells as hole transport materials (HTM), and the state-of-the art material used as hole transport material in perovskite solar cells: the spiro-OMeTAD. The observed differences in solar cell efficiencies are studied in depth using advanced photoinduced spectroscopic techniques under working illumination conditions. We have observed that there is no correlation between the highest occupied molecular orbital (HOMO) energy levels of the organic semiconductors and the measured open-circuit voltage (VOC). For instance, spiro-OMeTAD and P3HT have a comparable HOMO level of ~5.2 eV vs vacuum even though a difference in VOC of around 200 mV is recorded. This difference is in good agreement with the shift observed for the charge vs voltage measurements. Moreover, hole transfer from the perovskite to the HTM, estimated qualitatively from fluorescence quenching and emission lifetime, seems less efficient for the polymeric HTMs. Finally, the recombination currents from all devices were estimated by using the measured charge (calculated using photoinduced differential charging) and the carriers' lifetime and their value resulted in accordance with the registered short-circuit currents (JSC) at 1 sun.


Predictive efficacy of motion sickness history for airsickness.
Airsickness is a common problem in the early stage of flying training. It can be sufficiently severe to impair the student's flight performance and his ability to learn. Without adequate evaluation and rehabilitation, intractable airsickness symptoms will force student pilots to be permanently grounded. The purpose of this study was to evaluate the predictive efficacy of motion sickness history for airsickness of flight students. A motion sickness history questionnaire with four different scores was used to predict airsickness of student pilots in the Air Force Academy. The questionnaire asked subjects questions about the severity and frequency of motion sickness symptom experienced in nine different motion sickness situations before and after 12 years of age. The results were grouped to four different scores. Pearson correlation and Student's t-test methods were used to evaluate the correlations of the four different scores. A total of 76 flight students in the class of 1997 who had under gone their flight-training course were included in this study. They were all healthy males with a mean age of 22.2 years (range, 20-24 years). The airsickness incidence of student pilots was 50%. The four different scores of motion sickness history questionnaire were highly correlated (r = 0.69-0.86, p < 0.01). The "after 12 years-of-age actually sick" score key had greater predictive validity for airsickness than the other motion sickness history questionnaire score keys and so did the "before 12 years-of-age feels sick" and "after 12 years-of-age feels sick" for no airsickness. The motion sickness history questionnaire was an efficient method to predict airsickness among Air Force student pilots.


Building the foundation to generate a fundamental care standardised data set.
This paper provides an overview of the current state of performance measurement, key trends and a methodological approach to leverage in efforts to generate a standardised data set for fundamental care. Considerable transformation is occurring in health care globally with organisations focusing on achieving the quadruple aim of improving the experience of care, the health of populations, and the experience of providing care while reducing per capita costs of health care. In response, healthcare organisations are employing performance measurement and quality improvement methods to achieve the quadruple aim. Despite the plethora of measures available to health managers, there is no standardised data set and virtually no indicators reflecting how patients actually experience the delivery of fundamental care, such as nutrition, hydration, mobility, respect, education and psychosocial support. Given the linkages of fundamental care to safety and quality metrics, efforts to build the evidence base and knowledge that captures the impact of enacting fundamental care across the healthcare continuum and lifespan should include generating a routinely collected data set of relevant measures. This paper provides an overview of the current state of performance measurement, key trends and a methodological approach to leverage in efforts to generate a standardised data set for fundamental care. Standardised data sets enable comparability of data across clinical populations, healthcare sectors, geographic locations and time and provide data about care to support clinical, administrative and health policy decision-making.


Relationships among arteriolar, regional, and whole organ blood flow in cremaster muscle.
The relationship between microvessel and tissue blood flow (BF) was determined with two different techniques during changes in local vasomotor tone in the rat cremaster muscle. Whole organ and regional BF were measured with the radioactive microsphere technique (BFms) and compared with values calculated in individual arterioles (BFc) using the dual-slit cross-correlation technique. In the muscle prepared for microcirculatory observation (i.e., dissected, surgically divided into a flattened sheet, and covered with clear plastic), resting BFms was 43 +/- 3 ml X min-1 X 100 g-1, which was significantly higher than paired BFms in the contralateral undisturbed muscle (24 +/- 7 ml X min-1 X 100 g-1). Over a range in vasomotor tone, regional BFms to the edge of the tissue, which was exposed to the trauma of the surgery, was 56 +/- 7 ml X min-1 X 100 g-1 compared with 38 +/- 5 in the less traumatized center region, a significant difference of 79 +/- 31%. There was no linear relationship between arteriolar BFc and BFms. The correlation was not improved if the factors of vessel size, vasomotor tone, animal size, or muscle size were considered. Changes in arteriolar BFc (y) overestimated changes in total tissue BFms (x) by a factor of 2 (y = 2.01x - 0.6; r = 0.86), but changes in arteriolar BFc were proportional to changes in BFms if only the center region (x) of the tissue was considered (y = 1.08x - 0.1; r = 0.84). The general implication from these results is that factors that influence perfusion heterogeneity, such as surgical trauma, should be carefully considered when correlating macro- and microcirculatory measurements of BF.


Coupling of theta oscillations between anterior and posterior midline cortex and with the hippocampus in freely behaving rats.
Theta oscillations in the hippocampus support cognitive processing. Theta-range rhythmicity has also been reported in frontal and posterior cortical areas--where it tends to show consistent phase-relations with hippocampal rhythmicity. Theta-range rhythmicity may, then, be important for cortico-cortical and/or cortico-hippocampal interactions. Here, we surveyed the rat frontal and posterior midline cortices for theta-related oscillations and examined their relationships with hippocampal activity in freely moving rats. Variation in electroencephalography across 4 general classes of spontaneous behavior demonstrated different profiles of theta-like activities through the rat midline cortices. Analysis of cortico-cortical and cortico-hippocampal coherences showed distinct, behavior-dependent, couplings of theta and delta oscillations. Increased theta coherence between structures was most obvious during nonautomatic behaviors and least during immobility or grooming. Extensive coupling of theta oscillations throughout the rat midline cortices and hippocampus occurred during rearing, and exploratory behavior. Such increases in coherence could reflect binding of cortico-hippocampal pathways into temporary functional units by behavioral demands. Extensive coupling of frontal delta, which lacked coherence with posterior areas (including the hippocampus), suggests that different frequencies of rhythmicity may act to bind groups of structures into different functional circuits on different occasions.


Interannual Changes in the Prevalence of Intimate Partner Violence Against Pregnant Women in Miyagi Prefecture After the Great East Japan Earthquake: The Japan Environment and Children's Study.
This study aimed to clarify the interannual changes in intimate partner violence against pregnant women after the March 11, 2011 Great East Japan Earthquake in target areas of Miyagi Prefecture that were damaged by the earthquake and tsunami. Because of this disaster, in Miyagi Prefecture, approximately 12,000 people died or went missing, and approximately 238,000 buildings were destroyed. According to the U.S. Geological Survey, the Great East Japan Earthquake is the fourth largest earthquake in the world and the largest in Japan since 1900. The present study was part of the Japan Environment and Children's Study. Data from June 2011 to May 2014 of 79,222 pregnant women were analyzed, calculating the prevalence of physical and mental intimate partner violence in the inland, north coastal, and south coastal areas of Miyagi. These prevalence rates were compared with nationwide rates of intimate partner violence in 2011 using univariate and logistic regression analyses. After the disaster, the incidence of mental intimate partner violence increased in the south coastal area and then improved later (19.4%, 13.1%, and 13.3% for south coastal area, and 13.8%, 13.8%, and 13.1% for nationwide in 2011, 2012, and 2013, respectively). However, in the north coastal area, the incidence of physical intimate partner violence increased after the disaster and then improved later (2.7%, 1.5%, and 1.3% for north coastal area, and 1.4%, 1.3%, and 1.1% for nationwide in 2011, 2012, and 2013, respectively). In the inland area, however, the prevalence of both mental and physical intimate partner violence was consistently higher than nationwide rates after the disaster.


The role of endoplasmic reticulum stress, mitochondrial dysfunction and their crosstalk in intervertebral disc degeneration.
Low back pain (LBP) is a pervasive global health issue. Roughly 40% of LBP cases are attributed to intervertebral disc degeneration (IVDD). While the underlying mechanisms of IVDD remain incompletely understood, it has been confirmed that apoptosis and extracellular matrix (ECM) degradation caused by many factors such as inflammation, oxidative stress, calcium (Ca2+) homeostasis imbalance leads to IVDD. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are involved in these processes. The initiation of ER stress precipitates cell apoptosis, and is also related to inflammation, levels of oxidative stress, and Ca2+ homeostasis. Additionally, mitochondrial dynamics, antioxidative systems, disruption of Ca2+ homeostasis are closely associated with Reactive Oxygen Species (ROS) and inflammation, promoting cell apoptosis. However, numerous crosstalk exists between the ER and mitochondria, where they interact through inflammatory cytokines, signaling pathways, ROS, or key molecules such as CHOP, forming positive and negative feedback loops. Furthermore, the contact sites between the ER and mitochondria, known as mitochondria-associated membranes (MAM), facilitate direct signal transduction such as Ca2+ transfer. However, the current attention towards this issue is insufficient. Therefore, this review summarizes the impacts of ER stress and mitochondrial dysfunction on IVDD, along with the possibly potential crosstalk between them, aiming to unveil novel avenues for IVDD intervention.


Biliary cystadenomas: a case for complete resection.
Introduction and Objective. Biliary cystadenoma is a rare benign neoplasm of the liver with less than 200 cases being reported allover the world. We report a series of 13 cases highlighting the radiological findings and problems related to its management. Materials and Methods. Records of thirteen patients who underwent surgery for biliary cystadenomas, between March 2006 and October 2011, were reviewed retrospectively. Results. Majority of the patients were females (11 out of 13), with a median age of 46 (23-65) years. The most frequent symptom was abdominal pain (92%). Seven patients had presented with history of previous surgery for liver lesions. Five patients had presented with recurrence after partial resection for a suspected hydatid cyst and two after surgery for presumed simple liver cyst. Ten of the 13 patients had complete resection of the cyst with enucleation in 3 patients, 2 of whom in addition required T-tube drainage of the bile duct. There has been no recurrence during the follow-up period ranging from 3 months to 5 years. Conclusion. Biliary cystadenoma must be differentiated from other benign cysts. Hepatic resection or cyst enucleation is the recommended treatment option.


Management of secondary lymphedema related to breast cancer.
AbstractOBJECTIVE To review recent literature on the management of secondary lymphedema following breast cancer.QUALITY OF EVIDENCE MEDLINE, EMBASE, AMED, PubMed,and the Internet were searched for articles published between 2005 and 2009. Articles were evaluated using Sackett's levels of evidence. The literature search focused on primary research and systematic reviews.MAIN MESSAGE Secondary lymphedema related to breast cancer is an ongoing challenge. Evidence suggests that there are several safe and beneficial treatments, including complex decongestive therapy, physiotherapy, and exercise. Furthermore, resistive exercises,previously contraindicated on the affected side, have been found to be both beneficial and safe with careful progression and monitoring. Exercise guidelines and patient education topics are presented with a comprehensive reference list for further reading.CONCLUSION Advances in cancer treatment, cancer and exercise research, and lymphedema management require that physicians have a basic understanding of the current evidence to provide appropriate patient education and referral.


Peripheral artery disease and genetics: is there a cause-and-effect relationship?
Peripheral artery disease (PAD) is a major health problem worldwide, affecting millions of patients. Although cardiovascular risk factors, such as diabetes, tobacco use, hypertension, and hypercholesterolemia have been associated with the development of PAD, the possible existence of an inherited genetic predisposition to PAD has been investigated in numerous familial aggregation studies. A link between genetics and PAD may open new avenues for the prevention of this morbid and mortal disorder. This is an overview of the potential association between genetics and PAD.


Contrast-media-induced nephrotoxicity: a consensus report. Contrast Media Safety Committee, European Society of Urogenital Radiology (ESUR).
The purpose of this study was, using consensus methodology, to document current understanding of contrast media nephrotoxicity (CMN) and to identify areas where there is disagreement or confusion. To draw up guidelines for avoiding CMN based on the current understanding of the condition established by the survey. One hundred sixty-four statements were mailed to 148 members of the European Society of Urogenital Radiology (ESUR) and to 48 experts in the field of CMN. They were asked about the definition, clinical features, predisposing factors and pathophysiology of CMN and about prophylactic measures. The importance of the statements was rated on a scale from 1 to 10 (1 least important, 10 most important). Fifty-three members (38%) and 23 experts (48%) responded. Both groups considered that an increase in serum creatinine that peaks within 3-4 days and a decrease in creatinine clearance are the most important (rating > 7) features of CMN. Enzymuria was not considered important (rating < 6). Pre-existing renal insufficiency, diabetic nephropathy, dehydration, congestive heart failure, concurrent administration of nephrotoxic drugs and the dose and type of contrast media were considered to be risk factors. Reduction in renal perfusion and damage to tubular cells were considered the main factors in the pathophysiology of CMN (rating > 6). Hydration and the use of low osmolar contrast media were thought to minimize the incidence of CMN (rating > 6). The majority of the responders (84.6% of members and 95.5% of experts) believe that the incidence of CMN in patients with normal renal function is less than 5%. Of the members, 62.5%, and 35.3% of experts, believe that the incidence of CMN is 20-30% in the presence of risk factors. There was disagreement about the definition of CMN, the threshold dose of contrast media above which renal complications may develop, the safe period between repeat injections, the relevance of contrast media renal retention shown on CT and whether contrast media have long-term effects on renal function. The survey showed good understanding of CMN among those who answered the questionnaires, although areas of disagreement remain which require further research. Simple guidelines are proposed.


Sensing with photoluminescent semiconductor quantum dots.
Fluorescent sensors benefit from high signal-to-noise and multiple measurement modalities, enabling a multitude of applications and flexibility of design. Semiconductor nanocrystal quantum dots (QDs) are excellent fluorophores for sensors because of their extraordinary optical properties. They have high thermal and photochemical stability compared to organic dyes or fluorescent proteins and are extremely bright due to their large molar cross-sections. In contrast to organic dyes, QD emission profiles are symmetric, with relatively narrow bandwidths. In addition, the size tunability of their emission color, which is a result of quantum confinement, make QDs exceptional emitters with high color purity from the ultra-violet to near infrared wavelength range. The role of QDs in sensors ranges from simple fluorescent tags, as used in immunoassays, to intrinsic sensors that utilize the inherent photophysical response of QDs to fluctuations in temperature, electric field, or ion concentration. In more complex configurations, QDs and biomolecular recognition moieties like antibodies are combined with a third component to modulate the optical signal via energy transfer. QDs can act as donors, acceptors, or both in energy transfer-based sensors using Förster resonance energy transfer (FRET), nanometal surface energy transfer (NSET), or charge or electron transfer. The changes in both spectral response and photoluminescent lifetimes have been successfully harnessed to produce sensitive sensors and multiplexed devices. While technical challenges related to biofunctionalization and the high cost of laboratory-grade fluorimeters have thus far prevented broad implementation of QD-based sensing in clinical or commercial settings, improvements in bioconjugation methods and detection schemes, including using simple consumer devices like cell phone cameras, are lowering the barrier to broad use of more sensitive QD-based devices.


The impact of mathematical proficiency on the number-space association.
A specific instance of the association between numerical and spatial representations is the SNARC (Spatial Numerical Association of Response Codes) effect. The SNARC effect describes the finding that during binary classification of numbers participants are faster to respond to small/large numbers with the left/right hand respectively. Even though it has been frequently replicated, important inter-individual variability has also been reported. Mathematical proficiency is an obvious candidate source for inter-individual variability in numerical judgments, but studies investigating its influence on the SNARC effect remain scarce. The present experiment included a total of 95 University students, divided into three groups differing significantly in their mathematical proficiency levels. Using group analyses, it appeared that the three groups differed significantly in the strength of their number-space associations in a parity judgment task. This result was further confirmed on an individual level, with higher levels in arithmetic leading to relatively weaker SNARC effects. To explain this negative relationship we propose accounts based on differences in access to qualitatively different numerical representations and also consider more domain general factors, with a focus on inhibition capacities.


Morphology of the nutrient artery and its foramen in relation to femoral bone perfusion rates of laying and non-laying hens.
If arteries penetrate bones through foramina, regional artery blood flow rates can be estimated from the foramen sizes. Femoral bone blood flow rates estimated from nutrient foramen sizes were previously not absolute, but only a relative blood flow index (Qi ), because the size relationship between the foramen and the occupying artery was unknown. The current study used vascular contrast and micro-computerized tomographic scanning to investigate femoral nutrient foramen and nutrient artery sizes in three groups of sub-adult chickens (non-laying hens, laying hens, and roosters) of similar ages. The results indicate that the cross-sectional area of the nutrient artery lumen occupies approximately 20.2 ± 4.1% of the foramen for femora with only one foramen. Artery lumen size is significantly correlated with foramen size. Vascular contrast imaging is capable of estimating blood flow rates through nutrient arteries, as blood flow rates estimated from artery lumen casts are similar to blood flow rates measured by infusion of fluorescent-labeled microspheres. Laying hens tend to have higher nutrient artery perfusion rates than non-laying hens, probably due to extra oxygen and calcium requirements for eggshell production, although the calculated blood flow difference was not statistically significant. Histological embedding and sectioning along with vascular contrast imaging reveal variable nutrient foramen morphology and nutrient artery location among femora with more than one nutrient foramen.


Gamma band neural synchronization deficits for auditory steady state responses in bipolar disorder patients.
Periodic auditory click stimulation has been reported to elicit an auditory steady state response (ASSR). The ASSR has been suggested to reflect the efficiency of γ-amino butyric acid (GABA) inhibitory interneuronal activity. Although a potential role for GABAergic dysfunction has been previously proposed, the role of neural synchronization in the ASSR in people with bipolar disorder (BD) has received little attention. In the current study, we investigated ASSRs to 20 Hz, 30 Hz, 40 Hz and 80 Hz click trains in BD patients. A total of 14 (4 males) BD patients and 25 (10 males) healthy controls participated in this study. ASSRs were obtained using whole-head 306-channel magnetoencephalography to calculate, ASSR power values and phase locking factors (PLF). BD patients exhibited significantly reduced mean ASSR power and PLF values bilaterally at frequencies of 30, 40, and 80 Hz (p<0.05 for these frequencies). At 20 Hz, bipolar patients showed no significant reduction in mean ASSR power and PLF values. There was a significant negative correlation between 80 Hz-ASSR-power values obtained from the right hemisphere and scores on the Hamilton Depression Rating Scale (rho = -0.86, p = 0.0003). The current study showed reduced low and high gamma band ASSR power and PLF bilaterally with no significant beta band ASSR reduction in BD patients. BD patients are characterized by deficits in gamma band oscillations, which may be associated with GABA inhibitory interneuronal activity dysfunction.


Evaluating the agreement between different substance use recall periods in multiple HIV cohorts.
This study aims to evaluate the agreement in substance use on both binary and ordinal scales between 3-month and 6-month recall periods with samples from different communities, demographic backgrounds, and HIV status. We administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) to 799 participants from three different North American cohorts focused on substance use and HIV. We conducted a within-person agreement analysis by calculating the agreement levels and Kappa statistic between data collected using the 3-month recall ASSIST and 6-month custom substance use surveys as well as different terminology for each substance in multiple cohorts. For all drugs studied, the agreement on the binary use or ordinal frequency of use metrics showed a high agreement level between 80.4% and 97.9% and an adequate adjusted kappa value between 0.61 and 0.96, suggesting substantial agreement. According to the agreement criteria we proposed, substance use data collected using different recall periods and with variation in drug names can be harmonized across cohorts. This study is the first to evaluate the feasibility of data harmonization of substance use by demonstrating high level of agreement between different recall periods in different cohorts. The results can inform data harmonization efforts in consortia where data are collected from cohorts using different questions and recall periods.


[Nitric monoxide and other indicators of free radical processes and antioxidant system in patients with mixed or monoinvasion of Opisthorhis and Metorchis].
As compared with healthy individuals, patients with mixed Opisthorhis and Metorchis invasion and/or Opisthorhis monoinvasion were found to have a considerable increase in the serum levels of nitric monoxide and malondialdehyde with the concurrent suppression of catalase activity and lipid antioxidant activity, which correlated with the blood accumulation of some toxic trace elements. The highest accumulation levels of toxic trace elements, as well as the indicators of free radical processes were detected in patients with the mixed invasion as compared with the Opisthorhis monoinvasion group, which appears to be directly related to the intensity of invasion.


Molecular identification of blaTEM gene of extended-spectrum beta-lactamase-producing Escherichia coli from healthy pigs in Malang district, East Java, Indonesia.
The increase and prevalence of multidrug-resistant bacteria in livestock animals are serious public health concerns. This study aimed to identify the presence of the blaTEM gene in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolated from rectal swabs of apparently healthy pigs in Malang District, East Java, Indonesia. A total of 120 rectal swab samples were collected from the pigs. The rectal swabs were screened for the presence of E. coli using standard microbiological identification procedures. The Kirby-Bauer disk diffusion method identified multidrug-resistant E. coli. Five different classes of antibiotics were used to identify multidrug-resistant isolates, including Ciprofloxacin, Trimethoprim, Tetracycline, Streptomycin, and Aztreonam. Multidrug-resistant E. coli isolates were characterized for the presence of ESBL using double-disk synergy test methods. The presence of blaTEM genes was determined using polymerase chain reaction methods. The results of this study indicated that 107 (89.2%) out of 120 samples analyzed were positive for E. coli isolates. A total of 32 (29.9%) E. coli isolates were identified to be multidrug-resistant and further subjected to molecular testing. The molecular analysis revealed (5; 15.6%) E. coli isolates to harbor the blaTEM gene. The results of this study revealed that pigs and products of pork origin must be considered a source of transmission of ESBL-producing E. coli to public health important under the food chain.


Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells.
GM3 synthase (ST3GAL5) is the first biosynthetic enzyme of a- and b-series gangliosides. Patients with GM3 synthase deficiency suffer severe neurological disability and deafness. Eight children (ages 4.1 ± 2.3 years) homozygous for ST3GAL5 c.694C>T had no detectable GM3 (a-series) or GD3 (b-series) in plasma. Their auditory function was characterized by the absence of middle ear muscle reflexes, distortion product otoacoustic emissions and cochlear microphonics, as well as abnormal auditory brainstem responses and cortical auditory-evoked potentials. In St3gal5(-/-) mice, stereocilia of outer hair cells showed signs of degeneration as early as postnatal Day 3 (P3); thereafter, blebs devoid of actin or tubulin appeared at the region of vestigial kinocilia, suggesting impaired vesicular trafficking. Stereocilia of St3gal5(-/-) inner hair cells were fused by P17, and protein tyrosine phosphatase receptor Q, normally linked to myosin VI at the tapered base of stereocilia, was maldistributed along the cell membrane. B4galnt1(-/-) (GM2 synthase-deficient) mice expressing only GM3 and GD3 gangliosides had normal auditory structure and function. Thus, GM3-dependent membrane microdomains might be essential for the proper organization and maintenance of stereocilia in auditory hair cells.


A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the "post-inflammatory brain syndrome" PIBS.
Post-concussion syndrome is an aggregate of symptoms that commonly present together after head injury. These symptoms, depending on definition, include headaches, dizziness, neuropsychiatric symptoms, and cognitive impairment. However, these symptoms are common, occurring frequently in non-head injured controls, leading some to question the existence of post-concussion syndrome as a unique syndrome. Therefore, some have attempted to explain post-concussion symptoms as post-traumatic stress disorder, as they share many similar symptoms and post-traumatic stress disorder does not require head injury. This explanation falls short as patients with post-concussion syndrome do not necessarily experience many key symptoms of post-traumatic stress disorder. Therefore, other explanations must be sought to explain the prevalence of post-concussion like symptoms in non-head injury patients. Many of the situations in which post-concussion syndrome like symptoms may be experienced such as infection and post-surgery are associated with systemic inflammatory responses, and even neuroinflammation. Post-concussion syndrome itself has a significant neuroinflammatory component. In this review we examine the evidence of neuroinflammation in post-concussion syndrome and the potential role systemic inflammation plays in post-concussion syndrome like symptoms. We conclude that given the overlap between these conditions and the role of inflammation in their etiologies, a new term, post-inflammatory brain syndromes (PIBS), is necessary to describe the common outcomes of many different inflammatory insults. The concept of post-concussion syndrome is in its evolution therefore, the new term post-inflammatory brain syndromes provides a better understanding of etiology of its wide-array of symptoms and the wide array of conditions they can be seen in.


Class B beta-lactamases: the importance of being metallic.
The structural and functional features of class B b-lactamases, which are metal-dependent, are reviewed in this article. Enzymes from different bacterial strains exhibit a common fold and sequence similarity in their active sites. However, the protein scaffold fine tunes the metal binding affinity and substrate selectivity. In this way, some metallo-b-lactamases seem to be functional with only one Zn(II) equivalent per enzyme, whereas others require a binuclear active site. The sequence similarity leads to a subdivision of these enzymes into three subclasses. The substrate specificities are rather broad, except for enzymes belonging to subclass B2. Some inhibitors have been designed and tested, but none of them is able to exhibit a broad spectrum against these enzymes.


Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication.
Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1-infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1-induced interferon-alpha (IFN-α) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1-associated immune activation observed. T-cell and dendritic cell populations were isolated from treatment-naive chronically HIV-1-infected individuals enrolled in the Adult Clinical Trials Group 384 by fluorescence-activated cell sorting. The expression of 98 genes involved in Toll-like receptor and type I IFN signaling pathways were quantified using Nanostring technology. Several ISGs were significantly correlated with HIV-1 viral load and/or CD4(+) T-cell count. Higher expression levels of a subset of these ISGs were observed in cells derived from females as compared to males after adjusting for viral load and were correlated to higher levels of T-cell activation. These data show that higher IFN-α production is associated with higher ex vivo expression of several ISGs in females. This might contribute to higher levels of immune activation and the observed faster HIV-1 disease progression in females for a given level of viral replication.


Mesenchymal stromal cell response to intervertebral disc-like pH is tissue source dependent.
Intervertebral disc (IVD) degeneration (IVDD) has become increasingly prevalent and is a common contributing factor to low back pain. Current treatment options are limited to either symptom management or surgery. A promising treatment option being explored is intradiscal administration of mesenchymal stromal cells (MSCs). However, there remains a gap in knowledge as to whether MSCs from different tissue sources have similar responses to the low pH microenvironment of the IVD and the possible mechanisms governing these responses. To study this, MSCs from three different tissue sources: adipose (ADMSC), bone marrow (BMMSC), and amnion (AMMSC) were cultured at low pHs representative of IVDD. MSCs were assessed for survival, senescence, apoptosis, metabolic activity, and cytokine release profile. Additionally, western blot was utilized to assess Acid Sensing Ion Channel (ASIC) 1 and 3 expression. The results of this study indicated that MSC viability, cell proliferation, senescence, and metabolic activity is negatively affected by low pH and alters MSC cytokine production. This study also demonstrated that MSCs behavior is dependent on tissue source. Understanding how MSC behavior is altered by pH will allow further research aimed at increasing the efficacy of MSC therapy to promote in situ IVD tissue regeneration to combat IVDD. This article is protected by copyright. All rights reserved.


Nop2p is required for pre-rRNA processing and 60S ribosome subunit synthesis in yeast.
To investigate the function of the nucleolar protein Nop2p in Saccharomyces cerevisiae, we constructed a strain in which NOP2 is under the control of a repressible promoter. Repression of NOP2 expression lengthens the doubling time of this strain about fivefold and reduces steady-state levels of 60S ribosomal subunits, 80S ribosomes, and polysomes. Levels of 40S subunits increase as the free pool of 60S subunits is reduced. Nop2p depletion impairs processing of the 35S pre-rRNA and inhibits processing of 27S pre-rRNA, which results in lower steady-state levels of 25S rRNA and 5.8S rRNA. Processing of 20S pre-rRNA to 18S rRNA is not significantly affected. Processing at sites A2, A3, B1L, and B1S and the generation of 5' termini of different pre-rRNA intermediates appear to be normal after Nop2p depletion. Sequence comparisons suggest that Nop2p may function as a methyltransferase. 2'-O-ribose methylation of the conserved site UmGm psi UC2922 is known to take place during processing of 27S pre-rRNA. Although Nop2p depletion lengthens the half-life of 27S pre-RNA, methylation of UmGm psi UC2922 in 27S pre-rRNA is low during Nop2p depletion. However, methylation of UmGm psi UC2922 in mature 25S rRNA appears normal. These findings provide evidence for a close interconnection between methylation at this conserved site and the processing step that yields the 25S rRNA.


3D Bioprinting of Tissue/Organ Models.
In vitro tissue/organ models are useful platforms that can facilitate systematic, repetitive, and quantitative investigations of drugs/chemicals. The primary objective when developing tissue/organ models is to reproduce physiologically relevant functions that typically require complex culture systems. Bioprinting offers exciting prospects for constructing 3D tissue/organ models, as it enables the reproducible, automated production of complex living tissues. Bioprinted tissues/organs may prove useful for screening novel compounds or predicting toxicity, as the spatial and chemical complexity inherent to native tissues/organs can be recreated. In this Review, we highlight the importance of developing 3D in vitro tissue/organ models by 3D bioprinting techniques, characterization of these models for evaluating their resemblance to native tissue, and their application in the prioritization of lead candidates, toxicity testing, and as disease/tumor models.


Working memory capacity moderates the predictive effects of drug-related associations on substance use.
Some theories suggest that spontaneously activated, drug-related associations in memory may have a "freer reign" in predicting drug use among individuals with lower working memory capacity. This study evaluated this hypothesis among 145 at-risk youth attending continuation high schools (CHS). This is the 1st study to evaluate this type of dual-process interaction in the prediction of drug use among a sample of at-risk adolescents. The CHS students completed assessments of drug-related memory associations, working memory capacity, and drug use. Control variables included age, gender, ethnicity, and acculturation. Robust multiple regression using least trimmed squares estimation indicated that there was a significant linear by linear interaction between working memory capacity (assessed with the self-ordered pointing task) and drug-related associations (assessed with verb generation and cue-behavior association tasks) in the prediction of alcohol and cigarette use. Consistent with dual-process cognitive theories, drug-related associations in memory predicted drug use more strongly in students with lower levels of working memory capacity. These findings add to the literature implicating the influence of dual cognitive processes in adolescent risk behaviors.


Post-translational modifications and the Warburg effect.
Post-translational modification (PTM) is an important step of signal transduction that transfers chemical groups such as phosphate, acetyl and glycosyl groups from one protein to another protein. As most of the PTMs are reversible, normal cells use PTMs as a 'switch' to determine the resting and proliferating state of cells that enables rapid and tight regulation of cell proliferation. In cancer cells, activation of oncogenes and/or inactivation of tumor suppressor genes provide continuous proliferative signals in part by adjusting the state of diverse PTMs of effector proteins that are involved in regulation of cell survival, cell cycle and proliferation, leading to abnormally fast proliferation of cancer cells. In addition to dysregulated proliferation, 'altered tumor metabolism' has recently been recognized as an emerging cancer hallmark. The most common metabolic phenotype of cancer is known as the Warburg effect or aerobic glycolysis that consists of increased glycolysis and enhanced lactate production even in the presence of oxygen. Although Otto Warburg observed aerobic glycolysis nearly 90 years ago, the detailed molecular mechanisms how increased glycolysis is regulated by oncogenic and/or tumor suppressive signaling pathways remain unclear. In this review, we summarize recent advances revealing how these signaling pathways reprogram metabolism through diverse PTMs to provide a metabolic advantage to cancer cells, thereby promoting tumor cell proliferation, tumorigenesis and tumor growth.


Ovarian adenomyoma associated with an endometriotic cyst.
An adenomyoma was found in an endometriotic cyst of the right ovary of a 36-year-old woman. We have not seen a previous report of this entity. The most likely source of the smooth muscle component of this tumor is from within endometrial tissue lining the cyst.


Autotransplants in leukemia: current state, future progress.
Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?


Two new Ophiostoma species with Sporothrix anamorphs from Austria and Azerbaijan.
The genus Ophiostoma includes numerous species of primarily insect-vectored, wood-staining fungi. Several anamorph genera that differ in their micronematous or macronematous conidiogenous cells have been associated with Ophiostoma species. Among the former group, Sporothrix is associated with many species and is characterized by conidiogenous cells that arise laterally or terminally from any place on the hyphae and produce nonseptate conidia on sympodially developing denticles. The purpose of this study was to characterize ophiostomatoid isolates with Sporothrix anamorphs recently collected in Austria and Azerbaijan. The isolates were characterized based on comparisons of rDNA and β-tubulin sequence data. Morphology, growth in culture, and sexual reproductive mode were also considered. Phylogenetic analyses of the combined sequence data showed that the isolates formed two distinct groups, one including isolates from Austria and the other isolates from Austria and Azerbaijan. Growth at 25 C and morphology revealed some differences between the two groups, and supported the view that they represent two new species, which we describe here as Ophiostoma fusiforme sp. nov. and Ophiostoma lunatum sp. nov. Both these groups phylogenetically were related to, but distinct from, Ophiostoma stenoceras.


Medication regimen complexity and hospital readmission for an adverse drug event.
Adverse drug events (ADEs) are costly, dangerous, and often preventable. Little is known about the link between medication regimen complexity and rehospitalization as a result of an ADE. The objective of this study was to compare admission and discharge medication regimen complexity in 2 cohorts: patients readmitted for an ADE within 30 days and patients not readmitted for an ADE. The study used a retrospective parallel-group case-control design. Participants from 4 urban acute care hospitals were included in the revisit cohort if they were rehospitalized within 30 days as a result of an adverse event coded as accidental poisoning. The no-revisit cohort was formed by randomly sampling patients with the same disease classification codes as the revisit group but without history of a readmission within 30 days. Complexity of medication regimens at the initial admission and discharge was quantified with the medication regimen complexity index (MRCI). The revisit group comprised 92 individuals and the no-revisit group, 228. The revisit group had a significantly higher MRCI score at admission and discharge than the no-revisit group (all P < .005). Receiver operating characteristic curves, used to determine a potential MRCI cutoff score for risk of an ADE, revealed MRCI scores of 8 or greater to optimally predict increased risk for readmission caused by an ADE. Complex medication regimens at hospital admission are predictive of rehospitalizations for ADEs. This finding suggests that medication regimen complexity be considered as a target for interventions to decrease the risk for readmission.


Changing levels of sex hormones and calcitonin gene-related peptide (CGRP) during a woman's life: Implications for the efficacy and safety of novel antimigraine medications.
Migraine is a neurovascular disorder that is three times more prevalent in women than in men and represents a large socio-economic burden. Therefore, the development of new preventive medications is an urgent matter. Currently, calcitonin gene-related peptide (CGRP), a neuropeptide released from trigeminal fibres, is an important target for migraine treatment. Accordingly, antibodies directed against CGRP or its receptor, as well as small-molecule CGRP receptor antagonists, have been developed for the prophylactic and acute treatment of migraine. Results from clinical phase III trials show a significant decrease in migraine days and relatively mild side-effects. However, CGRP is not only present in the trigeminal nerve, but it is also abundant in perivascular nerve fibres. Moreover, CGRP levels and hormones vary between sexes and during different life stages, and hormones affect CGRP, with a seemingly greater role for CGRP in females. In this review we discuss whether these aspects could be associated with differences in response and efficacy of drugs interfering with the CGRP pathway. Furthermore, CGRP has been described as playing a protective role in ischemic events, and CGRP seems to play a larger role in cardiac ischemic events in female patients. As cardiovascular risk is increased in female migraine patients and also increases significantly in females after menopause, further research into the risk of blocking CGRP in these patients is needed.


Effects of laboratory salmon louse infection on osmoregulation, growth and survival in Atlantic salmon.
Anadromous Atlantic salmon (Salmo salar) rely on long ocean migrations to build energy stores for maturation and spawning. In seawater, wild Atlantic salmon are threatened by high salmon lice (Lepeophtheirus salmonis) infestation levels resulting from intensive salmonid sea-cage aquaculture. Salmon lice infection can cause a stress response and an osmotic imbalance in the host. The lice infection intensity threshold values for these responses, however, remain to be identified in Atlantic salmon. In order to define this under laboratory conditions, individually tagged F1 wild origin Atlantic post-smolts (40 g) were infected with salmon lice copepodids or left as uninfected controls. Twenty-eight days post infection, infected post-smolts had a mean of 0.38 (range of 0.07-0.9) mobile lice g-1 fish weight. During this period, specific growth rates (SGRs) were lower in infected than control fish (0.4 vs 1.0% day-1). Higher plasma Na+, Cl- and osmolality in infected fish also indicate osmoregulatory impairment. SGR correlated negatively with plasma Na+, Cl-, osmolality and cortisol in the infected, but not in the control group. Infection intensity (lice g-1 fish) correlated positively with mortality rate and plasma Na+, Cl-, osmolality and cortisol and correlated negatively with SGR and condition factor. Calculated lice intensity threshold values for changes in plasma ions were 0.18 lice g-1 for plasma Cl-, and 0.22 lice g-1 for plasma Na+. Moribund infected fish occurred at infection intensities above 0.2 lice g-1, and these fish had extreme plasma Cl-, Na+, osmolality and cortisol levels. There was a positive correlation between plasma cortisol and plasma Na+, Cl- and osmolality in infected fish. This study provides vital information that can be used to define thresholds in the monitoring and conservation of wild Atlantic salmon populations affected by aquaculture-driven salmon lice infestations.


Hexuronate catabolism in Erwinia chrysanthemi.
In the phytopathogenic enterobacterium Erwinia chrysanthemi, the catabolism of hexuronates is linked to the degradation of pectic polymers. We isolated Mu lac insertions in each gene of the hexuronate pathway and used genetic fusions with lacZ (the beta-galactosidase gene of Escherichia coli) to study the regulation of this pathway. Three independent regulatory genes (exuR, uxuR, and kdgR) were found. Galacturonate and glucuronate were converted into 2-keto-3-deoxygluconate (KDG) by separate three-step pathways encoded by the uxaC, uxaB, and uxaA genes and the uxaC, uxuB, and uxuA genes, respectively. The two aldohexuronates entered the cell by a specific transport system, encoded by exuT. Wild-type strain 3937 was unable to use glucuronate as a carbon source since glucuronate was unable to induce the exuT expression. Mutants able to use glucuronate possessed an inactivated exuR gene. The product of the regulatory gene exuR negatively controlled the expression of exuT, uxaC, uxaB, and uxaA, which was inducible in the presence of galacturonate. The two genes specifically involved in glucuronate catabolism, uxuA and uxuB, formed two independent transcriptional units regulated separately, uxuB expression was not inducible, whereas uxuA expression was induced in the presence of glucuronate and controlled by the uxuR product. KDG, the common end product of both pathways, is cleaved by the kdgK and kdgA gene products. KDG enters the cell by a specific transport system, encoded by kdgT. The regulatory gene kdgR controlled the expression of kdgT, kdgK, and kdgA and partially that of the pel genes encoding pectate-lyases. The real inducer of pectate-lyase synthesis, originating from catabolism of galacturonate or glucuronate, appeared to be KDG. The genes of E. chrysanthemi affecting hexuronate catabolism are separated into six independent transcriptional units exuT, uxaCBA, uxuA, uxuB, kdgK, and kdgA, but only three gene clusters were localized on the genetic map: exuT-uxaCBA, uxuA-uxuB-kdgK, and kdgA-exuR.


Genotypic variation and relationships among nitrogen-use efficiency and agronomic traits in tropical maize inbred lines.
Improvement in nitrogen-use efficiency (NUE) on maize is among the best strategies to mitigate the problems of poor soil fertility in tropical conditions. The objectives of this study were: i) to quantify the genetic variability for NUE-components and agronomic traits in a set of tropical maize inbred lines; ii) to study the genetic divergence among tropical maize inbred lines under contrasting nitrogen (N) levels; iii) to identify the secondary traits associated with NUE in tropical maize inbred lines; and iv) to identify maize inbred lines efficient in NUE and its components. Sixty-four tropical maize inbred lines were evaluated in the field under low- and high-N conditions for NUE-components and agronomic traits. Genetic variability for NUE-components and agronomic traits was found; lines in eight different groups for each N condition were allocated, and N-efficient inbred lines were identified in different groups. Furthermore, we suggest flowering time traits and kernel number as great secondary traits for selecting tropical maize inbred lines for NUE under both N conditions, and chlorophyll content for selecting for NUE under N stress.


One-year results from clinical practice of epimacular strontium-90 brachytherapy for the treatment of subfoveal choroidal neovascularization secondary to AMD.
To evaluate clinical feasibility, safety, and efficacy of epiretinal strontium-90 brachytherapy in subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD) in eyes unresponsive to repeated anti-VEGF injections. A retrospective, single-center study on patients treated with strontium-90 brachytherapy for CNV secondary to neovascular AMD. Patients underwent pars plana vitrectomy with a single 24 Gy dose brachytherapy. They were re-treated with anti-VEGF injections on an as-needed basis if subretinal or intraretinal fluid was detected on optical coherence tomography imaging. Twenty-two patients were treated, and 20 completed 12 months of follow-up. Ten patients maintained stable vision, eight gained vision, and two lost more than three Snellen lines. The mean best corrected visual acuity change from baseline was -8 ± 5.7 letters. A mean of 5.5 ± 4.4 anti-VEGF injections were administered throughout 12 months. Epimacular brachytherapy is feasible in clinical practice. While some patients benefit from the treatment and need significantly fewer as-needed injections, others appear not to react to irradiation treatment after 1 year of follow-up. Larger numbers of patients are needed to evaluate therapeutic efficacy and to determine which patients can benefit from combined radiation and anti-VEGF therapy.


Properties and biosynthesis of a neurotoxic protein of the venoms of s snakes Laticauda laticaudata and Laticauda colubrina.
1. A neurotoxic protein similar to erabutoxins a and b of Laticauda semifasciata was isolated in crystalline form from the venoms of Laticauda laticaudata and Laticauda colubrina. The name ;laticotoxin a' is proposed. 2. Laticotoxin a is homogeneous by CM-cellulose column chromatography, disc electrophoresis and ultracentrifugation and by terminal amino acid analyses. 3. Laticotoxin a consists of 62 amino acid residues. The molecular weight by ultracentrifuging is 6520. 4. The minimal 50% lethal dose of laticotoxin a by intramuscular injection to mice is 0.13mug./g. body wt. The toxin attacks the postsynaptic membrane, competing with acetylcholine. 5. Radioactive amino acids are incorporated into laticotoxin a in vivo. The incorporation is inhibited by puromycin, suggesting that the biosynthesis of the toxin follows the mechanism of protein biosynthesis, although the toxin molecule is rather small as a protein.


The mitochondrial genome is a "genetic sanctuary" during the oncogenic process.
Since Otto Warburg linked mitochondrial physiology and oncogenesis in the 1930s, a number of studies have focused on the analysis of the genetic basis for the presence of aerobic glycolysis in cancer cells. However, little or no evidence exists today to indicate that mtDNA mutations are directly responsible for the initiation of tumor onset. Based on a model of gliomagenesis in the mouse, we aimed to explore whether or not mtDNA mutations are associated with the initiation of tumor formation, maintenance and aggressiveness. We reproduced the different molecular events that lead from tumor initiation to progression in the mouse glioma. In human gliomas, most of the genetic alterations that have been previously identified result in the aberrant activation of different signaling pathways and deregulation of the cell cycle. Our data indicates that mitochondrial dysfunction is associated with reactive oxygen species (ROS) generation, leading to increased nuclear DNA (nDNA) mutagenesis, but maintaining the integrity of the mitochondrial genome. In addition, mutational stability has been observed in entire mtDNA of human gliomas; this is in full agreement with the results obtained in the cancer mouse model. We use this model as a paradigm of oncogenic transformation due to the fact that mutations commonly found in gliomas appear to be the most common molecular alterations leading to tumor development in most types of human cancer. Our results indicate that the mtDNA genome is kept by the cell as a "genetic sanctuary" during tumor development in the mouse and humans. This is compatible with the hypothesis that the mtDNA molecule plays an essential role in the control of the cellular adaptive survival response to tumor-induced oxidative stress. The integrity of mtDNA seems to be a necessary element for responding to the increased ROS production associated with the oncogenic process.


Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.
Cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increase their intestinal lymphatic transport in rats. CBD concentrations in the lymph were 250-fold higher than in plasma, while THC concentrations in the lymph were 100-fold higher than in plasma. Since cannabinoids are currently in clinical use for the treatment of spasticity in multiple sclerosis (MS) patients and to alleviate nausea and vomiting associated with chemotherapy in cancer patients, lymphocytes from those patients were used to assess the immunomodulatory effects of cannabinoids. The levels of cannabinoids recovered in the intestinal lymphatic system, but not in plasma, were substantially above the immunomodulatory threshold in murine and human lymphocytes. CBD showed higher immunosuppressive effects than THC. Moreover, immune cells from MS patients were more susceptible to the immunosuppressive effects of cannabinoids than those from healthy volunteers or cancer patients. Therefore, administering cannabinoids with a high-fat meal or in lipid-based formulations has the potential to be a therapeutic approach to improve the treatment of MS, or indeed other autoimmune disorders. However, intestinal lymphatic transport of cannabinoids in immunocompromised patients requires caution.


The molecular detection and clinical significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK targeted therapy.
This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients. ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation. The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival. Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.


Mla- and Rom1-mediated control of microRNA398 and chloroplast copper/zinc superoxide dismutase regulates cell death in response to the barley powdery mildew fungus.
• Barley (Hordeum vulgare L.) Mildew resistance locus a (Mla) confers allele-specific interactions with natural variants of the ascomycete fungus Blumeria graminis f. sp. hordei (Bgh), the causal agent of powdery mildew disease. Significant reprogramming of Mla-mediated gene expression occurs upon infection by this obligate biotrophic pathogen. • We utilized a proteomics-based approach, combined with barley mla, required for Mla12 resistance1 (rar1), and restoration of Mla resistance1 (rom1) mutants, to identify components of Mla-directed signaling. • Loss-of-function mutations in Mla and Rar1 both resulted in the reduced accumulation of chloroplast copper/zinc superoxide dismutase 1 (HvSOD1), whereas loss of function in Rom1 re-established HvSOD1 levels. In addition, both Mla and Rom1 negatively regulated hvu-microRNA398 (hvu-miR398), and up-regulation of miR398 was coupled to reduced HvSOD1 expression. Barley stripe mosaic virus (BSMV)-mediated over-expression of both barley and Arabidopsis miR398 repressed accumulation of HvSOD1, and BSMV-induced gene silencing of HvSod1 impeded Mla-triggered H₂O₂ and hypersensitive reaction (HR) at barley-Bgh interaction sites. • These data indicate that Mla- and Rom1-regulated hvu-miR398 represses HvSOD1 accumulation, influencing effector-induced HR in response to the powdery mildew fungus.


A decade of toxicogenomic research and its contribution to toxicological science.
Toxicogenomics enjoyed considerable attention as a ground-breaking addition to conventional toxicology assays at its inception. However, the pace at which toxicogenomics was expected to perform has been tempered in recent years. Next to cost, the lack of advanced knowledge discovery and data mining tools significantly hampered progress in this new field of toxicological sciences. Recently, two of the largest toxicogenomics databases were made freely available to the public. These comprehensive studies are expected to stimulate knowledge discovery and development of novel data mining tools, which are essential to advance this field. In this review, we provide a concise summary of each of these two databases with a brief discussion on the commonalities and differences between them. We place our emphasis on some key questions in toxicogenomics and how these questions can be appropriately addressed with the two databases. Finally, we provide a perspective on the future direction of toxicogenomics and how new technologies such as RNA-Seq may impact this field.


Effects of TCF7L2 polymorphisms on obesity in European populations.
The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele was previously associated with type 2 diabetes (T2D) and decreased BMI whereas haplotypes carrying the rs7903146 C and rs10885406 A alleles (HapA) were associated with increased BMI. The functional relevance of TCF7L2 polymorphisms and their effects on T2D and obesity remained to be further investigated. In white European populations, we found that the rs7903146 T allele was more associated with T2D in 3,547 non-obese individuals (odds ratio (OR) = 1.88 (1.69-2.10)) than in 1,110 class III obese subjects (OR = 1.24 (1.03-1.50)). No direct effect of the rs7903146 C allele and HapA was found on any form of obesity in 3,507 normal glucose tolerant (NGT) individuals, 1,106 pedigrees with familial obesity and 5,512 individuals from the French general population. However, in T2D subjects, the rs7903146 C allele was less prevalent in the 1,111 non-obese individuals (55.2%) compared to 659 class III obese subjects (67.5% OR = 1.69 (1.46-1.95)). Functional studies showed that the rs7903146 T allele is less prone to be bound by protein factors than the C allele in 3T3-L1, HepG2 and beta-TC3 cell lines and that TCF7L2 expression decreases in subcutaneous adipose tissue from NGT obese T/T carriers under calorie restriction. In conclusion, TCF7L2 is not a risk factor for obesity in European populations, but its effect on T2D risk is modulated by obesity. Furthermore, our data suggest that the rs7903146 T allele may be possibly functional and associated with a nominal decrease in TCF7L2 expression in adipose tissue of individuals under calorie restriction.


Effects of atriopeptin III on isolated mesenteric resistance vessels from SHR and WKY.
The effects of atriopeptin III (AP III) were determined on agonist-induced [i.e., 10(-4) M norepinephrine (NE)] and depolarization-induced (80 mM K+) contractions of isolated mesenteric resistance vessels (ID approximately 100 microns) from spontaneously hypertensive rats (SHR) and from normotensive control Wistar-Kyoto (WKY) rats. The vessels from both groups, when activated by 80 mM K+, were unaffected by AP III. However, activation of WKY vessels by 10(-4) M NE (both phasic and tonic contraction) was inhibited quite effectively and potently by AP III, whereas that in SHR vessels was much less inhibited. In the WKY rat vessels, the concentration of AP III that inhibited contraction by 50% for NE-induced phasic tension was 3.1 +/- 1.3 nM, whereas in SHR vessels it was nearly 1 microM. Comparison of AP III inhibition of NE-induced phasic tension to that at 5 min of activation (tonic tension) indicated that the tonic contractions were less sensitive to AP III than the phasic contractions in the vessels from both strains. A similar experiment indicated that AP III was a potent inhibitor of agonist-induced activation in a human renal resistance vessel (ID 125 microns) and that this vessel depended virtually completely on extracellular Ca2+ for NE-induced contraction. These studies contrast with earlier reports (1, 30) that similar peptides inhibited tension only in rat renal resistance vessels and not in resistance vessels from other vascular beds. The decreased sensitivity and efficacy of AP III in inhibiting tension in SHR compared with WKY mesenteric resistance vessels is discussed in the context of the etiology of spontaneous hypertension.


A novel antiinflammatory role for the short-chain fatty acids in human labor.
Human parturition is an inflammatory process that can be activated prematurely by pathological stimuli. This study investigated the expression of G protein-coupled receptors GPR43 and GPR41 receptors in human uteroplacental tissues and the role of short-chain fatty acids (SCFA) in modulating inflammatory pathways in fetal membranes. Expression of GPR43 and GPR41 was investigated in uteroplacental tissues collected from women delivering at term or preterm after ethical approval and patient informed consent. The effect of SCFA on expression of inflammatory genes was assessed in amnion explants after culture with a mimetic of infection (lipopolysaccharide, LPS). Sodium propionate effect on LPS-induced neutrophil chemotaxis was evaluated by transwell assay. GPR43 and GPR41 mRNA expression was higher in myometrium and fetal membranes collected from women after the onset of labor. GPR43 protein expression localized to immune cells and vascular endothelium in the myometrium and epithelium of fetal membranes. Treatment with LPS significantly increased mRNA expression of GPR43 and inflammatory genes. Cotreatment with LPS and sodium propionate decreased LPS-induced expression of inflammatory genes including IL-6, IL-8, cyclooxygenase-2, IL-1α, intercellular adhesion molecule-1, and platelet endothelial cell adhesion molecule-1 but not IL-1β or lymphocyte function-associated antigen-1. Sodium propionate reduced LPS-induced neutrophil chemotaxis and protein secretion of the neutrophil chemoattractant IL-8. Finally, fetal membrane expression of GPR43 was significantly higher in women delivering preterm with evidence of infection. GPR43-SCFA interactions may represent novel pathways that regulate inflammatory processes involved in human labor. Suppression of inflammatory pathways by SCFA may be therapeutically beneficial for pregnant women at risk of pathogen-induced preterm delivery.


Race, visceral adipose tissue, plasma lipids, and lipoprotein lipase activity in men and women: the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) family study.
Abdominal obesity is associated with numerous metabolic alterations, such as hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. However, compared with abdominally obese white individuals, abdominally obese black individuals have been characterized by higher plasma HDL cholesterol levels, suggesting that the impact of abdominal fat accumulation on the lipoprotein-lipid profile may differ among ethnic groups. Therefore, we have compared the associations between body fatness, visceral adipose tissue (AT) accumulation, and metabolic risk variables in a sample of 247 white men and 240 white women versus a sample of 93 black men and 143 black women. Although no difference in mean total body fatness was found between the 2 race groups, white men had higher levels of visceral AT than did black men (P<0.001). Despite the fact that black women had a greater body fat content than did white women, black women had levels of visceral AT that were similar to those of white women, suggesting a lower susceptibility to visceral obesity in black women. This lower accumulation of visceral AT in blacks was accompanied by significantly reduced apolipoprotein B concentrations and ratios of total cholesterol to HDL cholesterol as well as higher plasma HDL cholesterol levels (P<0.05) compared with those values in whites. Irrespective of sex, higher postheparin plasma hepatic lipase (HL) and lower lipoprotein lipase (LPL) activities were found in whites, resulting in an HL/LPL ratio that was twice as high in whites as in blacks (P<0.005). Although differences in lipoprotein-lipid levels were noted between whites and blacks, results from multiple regression analyses revealed that after control for morphometric and metabolic variables of the study (body fat mass, visceral AT, LPL, HL, and age), ethnicity had, per se, only a minor contribution to the variance in plasma lipoprotein levels. Thus, our results suggest that the higher plasma HDL cholesterol levels and the generally more cardioprotective plasma lipoprotein profile found in abdominally obese black versus white individuals are explained, at least to a certain extent, by a lower visceral AT deposition and a higher plasma LPL activity in black individuals.


Dimensions of the pet population problem.
In 1973, an estimated $4.5 billion was spent on the combined care and feeding of pets, whereas about 18 million neglected pets were impounded, costing our society nearly $125 million. About 72,000 dogs and cats must die or be killed each day to maintain zero growth in the population. Humane shelters and pounds have become slaughterhouses. Neglected pets constitute a hazard to the health and quality of life of man and other animals. Sizable segments of society are becomming hostile toward dogs and cats.


Glycogen synthase kinase 3 inhibition slows mitochondrial adenine nucleotide transport and regulates voltage-dependent anion channel phosphorylation.
Inhibition of glycogen synthase kinase (GSK)-3 reduces ischemia/reperfusion injury by mechanisms that involve the mitochondria. The goal of this study was to explore possible molecular targets and mechanistic basis of this cardioprotective effect. In perfused rat hearts, treatment with GSK inhibitors before ischemia significantly improved recovery of function. To assess the effect of GSK inhibitors on mitochondrial function under ischemic conditions, mitochondria were isolated from rat hearts perfused with GSK inhibitors and were treated with uncoupler or cyanide or were made anoxic. GSK inhibition slowed ATP consumption under these conditions, which could be attributable to inhibition of ATP entry into the mitochondria through the voltage-dependent anion channel (VDAC) and/or adenine nucleotide transporter (ANT) or to inhibition of the F(1)F(0)-ATPase. To determine the site of the inhibitory effect on ATP consumption, we measured the conversion of ADP to AMP by adenylate kinase located in the intermembrane space. This assay requires adenine nucleotide transport across the outer but not the inner mitochondrial membrane, and we found that GSK inhibitors slow AMP production similar to their effect on ATP consumption. This suggests that GSK inhibitors are acting on outer mitochondrial membrane transport. In sonicated mitochondria, GSK inhibition had no effect on ATP consumption or AMP production. In intact mitochondria, cyclosporin A had no effect, indicating that ATP consumption is not caused by opening of the mitochondrial permeability transition pore. Because GSK is a kinase, we assessed whether protein phosphorylation might be involved. Therefore, we performed Western blot and 1D/2D gel phosphorylation site analysis using phos-tag staining to indicate proteins that had decreased phosphorylation in hearts treated with GSK inhibitors. Liquid chromatographic-mass spectrometric analysis revealed 1 of these proteins to be VDAC2. Taken together, we found that GSK-mediated signaling modulates transport through the outer membrane of the mitochondria. Both proteomics and adenine nucleotide transport data suggest that GSK regulates VDAC and that VDAC may be an important regulatory site in ischemia/reperfusion injury.


Accelerated Vascular Aging as a Paradigm for Hypertensive Vascular Disease: Prevention and Therapy.
Aging is considered the most important nonmodifiable risk factor for cardiovascular disease and death after age 28 years. Because of demographic changes the world population is expected to increase to 9 billion by the year 2050 and up to 12 billion by 2100, with several-fold increases among those 65 years of age and older. Healthy aging and prevention of aging-related diseases and associated health costs have become part of political agendas of governments around the world. Atherosclerotic vascular burden increases with age; accordingly, patients with progeria (premature aging) syndromes die from myocardial infarctions or stroke as teenagers or young adults. The incidence and prevalence of arterial hypertension also increases with age. Arterial hypertension-like diabetes and chronic renal failure-shares numerous pathologies and underlying mechanisms with the vascular aging process. In this article, we review how arterial hypertension resembles premature vascular aging, including the mechanisms by which arterial hypertension (as well as other risk factors such as diabetes mellitus, dyslipidemia, or chronic renal failure) accelerates the vascular aging process. We will also address the importance of cardiovascular risk factor control-including antihypertensive therapy-as a powerful intervention to interfere with premature vascular aging to reduce the age-associated prevalence of diseases such as myocardial infarction, heart failure, hypertensive nephropathy, and vascular dementia due to cerebrovascular disease. Finally, we will discuss the implementation of endothelial therapy, which aims at active patient participation to improve primary and secondary prevention of cardiovascular disease.


Prostaglandins for preventing postpartum haemorrhage.
Prostaglandins have mainly been used for postpartum haemorrhage (PPH) when other measures fail. Misoprostol, a new and inexpensive prostaglandin E1 analogue, has been suggested as an alternative for routine management of the third stage of labour. To assess the effects of prophylactic prostaglandin use in the third stage of labour. The Cochrane Pregnancy and Childbirth Group's Trials Register (February 2007) and PubMed (July 2006). Randomized trials comparing a prostaglandin agent with another uterotonic or no prophylactic uterotonic (nothing or placebo) as part of management of the third stage of labour. The primary outcomes were blood loss 1000 ml or more and the use of additional uterotonics. Two review authors independently assessed eligibility and trial quality and extracted data. Thirty-seven misoprostol and nine intramuscular prostaglandin trials (42,621 women) were included. Oral (seven trials, 2849 women) or sublingual misoprostol (relative risk (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) compared to placebo may be effective in reducing severe PPH and blood transfusion (RR 0.31; 95% CI 0.10 to 0.94; five oral misoprostol trials, 3519 women). The severe PPH analysis of oral misoprostol trials was not totalled due to significant heterogeneity. Compared to conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.32; 95% CI 1.16 to 1.51; 16 trials, 29,042 women) and use of additional uterotonics but with fewer blood transfusions (RR 0.81; 95% CI 0.64 to 1.02; 15 trials, 27,858 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38 degrees Celsius. There are scarce data comparing injectable prostaglandins with the conventional injectable uterotonics on severe PPH and the use of additional uterotonics, the primary outcomes of this review. Misoprostol orally or sublingually at a dose of 600 mcg shows promising results when compared to placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of management of the third stage of labour are used or not. As side-effects are dose-related, research should be directed towards establishing the lowest effective dose for routine use, and the optimal route of administration. Neither intramuscular prostaglandins nor misoprostol are preferable to conventional injectable uterotonics as part of the management of the third stage of labour especially for low-risk women.


Functional implications of K63-linked ubiquitination in the iron deficiency response of Arabidopsis roots.
Iron is an essential micronutrient that plays important roles as a redox cofactor in a variety of processes, many of which are related to DNA metabolism. The E2 ubiquitin conjugase UBC13, the only E2 protein that is capable of catalyzing the formation of non-canonical K63-linked ubiquitin chains, has been associated with the DNA damage tolerance pathway in eukaryotes, critical for maintenance of genome stability and integrity. We previously showed that UBC13 and an interacting E3 ubiquitin ligase, RGLG, affect the differentiation of root epidermal cells in Arabidopsis. When grown on iron-free media, Arabidopsis plants develops root hairs that are branched at their base, a response that has been interpreted as an adaption to reduced iron availability. Mutations in UBC13A abolished the branched root hair phenotype. Unexpectedly, mutations in RGLG genes caused constitutive root hair branching. Based on recent results that link endocytotic turnover of plasma membrane-bound PIN transporters to K63-linked ubiquitination, we reinterpreted our results in a context that classifies the root hair phenotype of iron-deficient plants as a consequence of altered auxin distribution. We show here that UBC13A/B and RGLG1/2 are involved in DNA damage repair and hypothesize that UBC13 protein becomes limited under iron-deficient conditions to prioritize DNA metabolism. The data suggest that genes involved in combating detrimental effects on genome stability may represent essential components in the plant's stress response.