Appropriateness of the current guidelines on reperfusion treatment for patients applying to our hospital with ST-segment elevation acute myocardial infarction.
This study investigated the appropriateness of treatment for patients admitted with ST-segment elevation myocardial infarction (STEMI) according to the current guidelines. We also aimed to determine in-patient and out-patient factors affecting optimal reperfusion therapy. The reperfusion therapy of 176 patients with STEMI was determined. The time period from first contact with a healthcare provider to the time of balloon inflation (door to balloon time), and from the time period of first contact with a healthcare provider to the time of initiation of a thrombolytic (door to needle time) were calculated. Similarly, the time from admission at the emergency service (ES) of our hospital after referral to the moment of balloon inflation (ES to balloon time) and the period from admission to ES at our hospital to the moment of initiation of a thrombolytic (ES to needle time) were calculated. In order to determine the amount of in-hospital delay, the time from ES admission to the call to the cardiology department and the time for the cardiologist to evaluate the patient and transfer time were recorded. Whether the referring physician was a cardiologist and the effect of work hours on the reperfusion period was also recorded. The door to balloon time in the referred patient group was calculated as an average of 228 minutes, while the time for patients directly admitted to ES was calculated as an average of 98 minutes. Patients referred for the mechanical reperfusion period compared to American Heart Association (AHA) guidelines consisted of only 6% of the eligible patients, while according to the European Society of Cardiology (ESC) guidelines 13% of patients were appropriate. Patients who were directly admitted to ES, experienced rates according to AHA guidelines and 73% experienced these rates according to ESC guidelines. We also found no significant effect of working hours or referring physician's specialty (cardiologist or other) on reperfusion time. Compliance rates of reperfusion therapy for patients presenting with STEMI was very low. We realized, when taking into consideration the reasons for delay in terms of both health community and the policy of the country, it is obvious that we have to take strict measures.


Increased nonenzymatically glycosylated proteins in the vitreous humor of diabetic animals.
One of the earliest pathologic changes of diabetes mellitus is increased nonenzymatic glycosylation (i.e., glycation) of proteins, which results in abnormal aggregation of collagen fibrils and production of superoxide radicals. These abnormalities may be responsible for the precocious senescence of connective tissue associated with the disease. We sought to determine whether glycation is increased in the vitreous humor of short-term diabetic cats (6 months' duration) and rabbits (2 months' duration), using a nitroblue tetrazolium colorimetric assay for fructosamine. Vitreous protein fructosamine concentration was significantly higher in diabetic cats and rabbits, compared with that in control (nondiabetic) animals. These results indicate that glycation is increased in the vitreous humor of short-term diabetic animals, and therefore may be one of the initial triggers for clinically apparent diabetic retinopathy.


Has1 regulates consecutive maturation and processing steps for assembly of 60S ribosomal subunits.
Ribosome biogenesis requires ∼200 assembly factors in Saccharomyces cerevisiae. The pre-ribosomal RNA (rRNA) processing defects associated with depletion of most of these factors have been characterized. However, how assembly factors drive the construction of ribonucleoprotein neighborhoods and how structural rearrangements are coupled to pre-rRNA processing are not understood. Here, we reveal ATP-independent and ATP-dependent roles of the Has1 DEAD-box RNA helicase in consecutive pre-rRNA processing and maturation steps for construction of 60S ribosomal subunits. Has1 associates with pre-60S ribosomes in an ATP-independent manner. Has1 binding triggers exonucleolytic trimming of 27SA3 pre-rRNA to generate the 5' end of 5.8S rRNA and drives incorporation of ribosomal protein L17 with domain I of 5.8S/25S rRNA. ATP-dependent activity of Has1 promotes stable association of additional domain I ribosomal proteins that surround the polypeptide exit tunnel, which are required for downstream processing of 27SB pre-rRNA. Furthermore, in the absence of Has1, aberrant 27S pre-rRNAs are targeted for irreversible turnover. Thus, our data support a model in which Has1 helps to establish domain I architecture to prevent pre-rRNA turnover and couples domain I folding with consecutive pre-rRNA processing steps.


Strategies for primary and secondary stroke prevention in atrial fibrillation.
Atrial fibrillation (AF) is the most common type of cardiac rhythm abnormality in adults, affecting 1 to 1.5% of the general population in the Western world and is the major risk factor for stroke with a fivefold risk compared with the general population. Pharmacological and nonpharmacological strategies are available for controlling recurrent or permanent AF as well as for prevention of AF. Prevention of recurrent AF is one of the best protections against AF-related stroke and reduces the prevalence of stroke by almost 25%. Antiplatelet compounds are indicated for CHAD scores 0-1 and reduce the risk of stroke from AF by 20 to 25%. For CHAD scores >1 oral anticoagulation with vitamin K antagonists is indicated and reduces the risk of stroke by 62%. Since inhibitors of coagulation factors Xa, VII , or II a have either not been clinically tested for their efficacy for prevention of stroke from AF, did not show a comparable effect to well-established drugs, or had excess side effects (idraparinux, ximelagatran), and since mechanical devices are highly questionable concerning their long-term effect, there is currently no alternative to oral anticoagulation with vitamin K antagonists as primary or secondary stroke prevention in high-risk AF patients.


The Croonian Lecture, 1991. Genostasis and the limits to evolution.
The Darwinian explanation for evolution is that it is the outcome of the interaction between genetic variation and natural selection. There is now good evidence for both the existence of genetic variation and the occurrence of natural selection, the latter potentially at high intensities. The outcome should be rapid evolutionary change; yet in practice very little change is found. Most species are very stable, and in situations where evolution is observed in one species often none is found in others despite equivalent opportunity. Evolutionary failure is commonplace. Despite the occurrence of high levels of protein polymorphism, there is good evidence that the supply of variation making a major contribution to fitness is very limited. As a result it is argued that lack of evolution in most species may be due more to lack of appropriate variability than to other causes: a condition for which the term 'genostasis' is proposed. In those situations where appropriate genetic variation is available for one reason or another, evolution is found to be very rapid. There are good theoretical and practical reasons for more attention being paid to the mechanisms of supply of new variation and to those situations where evolution appears not be taking place.


Biosynthesis, membrane association, and release of N-CAM-120, a phosphatidylinositol-linked form of the neural cell adhesion molecule.
The neural cell adhesion molecule (N-CAM) of rodents comprises three distinct proteins of Mr 180,000, 140,000, and 120,000 (designated N-CAM-180, -140, and -120). They are expressed in different proportions by different tissues and cell types. but the individual contribution of each form to cell adhesion is presently unknown. Previous studies have shown that the two N-CAM species of higher relative molecular mass span the membrane whereas N-CAM-120 lacks a transmembrane domain and can be released from the cell surface by phosphatidylinositol-specific phospholipase C. In this report, we provided evidence that N-CAM-120 contained covalently bound phosphatidylinositol and studied N-CAM-120 from its biosynthesis to its membrane insertion and finally to its release from the cell surface. Evidence was presented showing that the lipid tail of N-CAM-120 contained ethanolamine as is the case for other lipid-linked molecules. The phospholipid anchor was attached to the protein during the first minutes after completion of the polypeptide chain. This process took place in the endoplasmic reticulum as judged from endoglycosidase H digestion experiments. Immediately after a 2-min pulse with [35S]methionine, we detected also a short-lived precursor that had not yet acquired the lipid tail. Pulse-chase studies established that N-CAM-120 was transported to the cell surface from which it was slowly released into the extracellular milieu. The molecules recovered in the incubation medium appeared to have lost all of their bound fatty acid but only around half of the ethanolamine. Upon fractionation of brain tissue, approximately 75% of N-CAM-120 was recovered with a membrane fraction and approximately 25% in a membrane-free supernatant. A small proportion (approximately 6%) was found to be resistant to extraction by non-ionic detergent. A major posttranslational modification of N-CAM is polysialylation. Our results showed that also N-CAM-120 was polysialylated in the young postnatal brain and released in this form from cultured cerebellar cells. The presence of N-CAM in a form that can be released from the cell surface and accumulates in the extracellular fluid suggests a novel mechanism by which N-CAM-mediated adhesion may be modulated.


Actions of external hypertonic urea, ADH, and theophylline on transcellular and extracellular solute permeabilities in frog skin.
Increases in transepithelial solute permeability were elicited in the frog skin with external hypertonic urea, theophylline, and vasopressin (ADH). In external hypertonic urea, which is known to increase the permeability of the extracellular (paracellular) pathway, the unidirectional transepithelial fluxes of Na (passive), K, Cl, and urea increased substantially while preserving a linear relationship to each other. The same linear relationship was also observed for the passive Na and urea fluxes in regular Ringer and under stimulation with ADH or 10 mM theophylline, indicating that their permeation pathway was extracellular. A linear relationship between Cl and urea fluxes could be demonstrated if the skins were separated according to their open circuit potentials; parallel lines were obtained with increasing intercepts on the Cl axis as the open circuit potential decreased. The slopes of the Cl vs. urea lines were not different from that obtained in external hypertonic urea, indicating that this relationship described the extracellular movement of Cl. The intercept on the ordinate was interpreted as the contribution from the transcellular Cl movement. In the presence of 0.5 mM theophylline or 10 mU/ml of ADH, mainly the transcellular movement of Cl increased, whereas 10 mM theophylline caused increases in both transcellular and extracellular Cl fluxes. These and other data were interpreted in terms of a possible intracellular control of the theophylline-induced increase in extracellular fluxes. The changes in passive solute permeability were shown to be independent of active transport. The responses of the active transport system, the transcellular and paracellular pathways to theophylline and ADH could be explained in terms of the different resulting concentrations of cyclic 3'-5'-AMP produced by each of these substances in the tissue.


Protective effects of myricetin on acute hypoxia-induced exercise intolerance and mitochondrial impairments in rats.
Exercise tolerance is impaired in hypoxia. The aim of this study was to evaluate the effects of myricetin, a dietary flavonoid compound widely found in fruits and vegetables, on acute hypoxia-induced exercise intolerance in vivo and in vitro. Male rats were administered myricetin or vehicle for 7 days and subsequently spent 24 hours at a barometric pressure equivalent to 5000 m. Exercise capacity was then assessed through the run-to-fatigue procedure, and mitochondrial morphology in skeletal muscle cells was observed by transmission electron microscopy (TEM). The enzymatic activities of electron transfer complexes were analyzed using an enzyme-linked immuno-sorbent assay (ELISA). mtDNA was quantified by real-time-PCR. Mitochondrial membrane potential was measured by JC-1 staining. Protein expression was detected through western blotting, immunohistochemistry, and immunofluorescence. Myricetin supplementation significantly prevented the decline of run-to-fatigue time of rats in hypoxia, and attenuated acute hypoxia-induced mitochondrial impairment in skeletal muscle cells in vivo and in vitro by maintaining mitochondrial structure, mtDNA content, mitochondrial membrane potential, and activities of the respiratory chain complexes. Further studies showed that myricetin maintained mitochondrial biogenesis in skeletal muscle cells under hypoxic conditions by up-regulating the expressions of mitochondrial biogenesis-related regulators, in addition, AMP-activated protein kinase(AMPK) plays a crucial role in this process. Myricetin may have important applications for improving physical performance under hypoxic environment, which may be attributed to the protective effect against mitochondrial impairment by maintaining mitochondrial biogenesis.


Structural brain changes versus self-report: machine-learning classification of chronic fatigue syndrome patients.
Chronic fatigue syndrome (CFS) is a disorder associated with fatigue, pain, and structural/functional abnormalities seen during magnetic resonance brain imaging (MRI). Therefore, we evaluated the performance of structural MRI (sMRI) abnormalities in the classification of CFS patients versus healthy controls and compared it to machine learning (ML) classification based upon self-report (SR). Participants included 18 CFS patients and 15 healthy controls (HC). All subjects underwent T1-weighted sMRI and provided visual analogue-scale ratings of fatigue, pain intensity, anxiety, depression, anger, and sleep quality. sMRI data were segmented using FreeSurfer and 61 regions based on functional and structural abnormalities previously reported in patients with CFS. Classification was performed in RapidMiner using a linear support vector machine and bootstrap optimism correction. We compared ML classifiers based on (1) 61 a priori sMRI regional estimates and (2) SR ratings. The sMRI model achieved 79.58% classification accuracy. The SR (accuracy = 95.95%) outperformed both sMRI models. Estimates from multiple brain areas related to cognition, emotion, and memory contributed strongly to group classification. This is the first ML-based group classification of CFS. Our findings suggest that sMRI abnormalities are useful for discriminating CFS patients from HC, but SR ratings remain most effective in classification tasks.


Development of the cardiac conduction system involves recruitment within a multipotent cardiomyogenic lineage.
The cardiac pacemaking and conduction system sets and maintains the rhythmic pumping action of the heart. Previously, we have shown that peripheral cells of the conduction network in chick (periarterial Purkinje fibers) are selected within a cardiomyogenic lineage and that this recruitment occurs as a result of paracrine cues from coronary arteries. At present, the cellular derivation of other elements of this specialized system (e.g. the nodes and bundles of the central conduction system) are controversial, with some proposing that the evidence supports a neurogenic and others a myogenic origin for these tissues. While such ontological questions remain, it is unlikely that progress can be made on the molecular mechanisms governing patterning and induction of the central conduction system. Here, we have undertaken lineage-tracing strategies based on the distinct properties of replication-incompetent adenoviral and retroviral lacZ-expressing constructs. Using these complementary approaches, it is shown that cells constituting both peripheral and central conduction tissues originate from cardiomyogenic progenitors present in the looped, tubular heart with no detectable contribution by migratory neuroectoderm-derived populations. Moreover, clonal analyses of retrovirally infected cells incorporated within any part of the conduction system suggest that such cells share closer lineage relationships with nearby contractive myocytes than with other, more distal elements of the conduction system. Differentiation birthdating by label dilution using [(3)H]thymidine also demonstrates the occurrence of ongoing myocyte conscription to conductive specialization and provides a time course for this active and localized selection process in different parts of the system. Together, these data suggest that the cardiac conduction system does not develop by outgrowth from a prespecified pool of 'primary' myogenic progenitors. Rather, its assembly and elaboration occur via processes that include progressive and localized recruitment of multipotent cardiomyogenic cells to the developing network of specialized cardiac tissues.


Development of a toolkit for early identification of cauda equina syndrome.
Aim To develop a simple cauda equina syndrome (CES) toolkit to facilitate the subjective examination of low back pain patients potentially at risk of CES. To undertake preliminary validation of the content of the toolkit. CES is a rare condition which can be very challenging to identify in a generalist medical setting. A three phase iterative design with two stake holder groups; extended scope practitioners experienced in managing CES patients and CES sufferers. Toolkit development Synthesis of existing CES literature with CES patient data generated from in depth interviews. Toolkit validation Content validation of the draft toolkit with CES patients. Toolkit validation Content validation of the draft toolkit with extended scope physiotherapists. Findings A three arm toolkit has been developed for use with patients considered by the clinician as at risk of developing CES (eg, worsening low back pain with symptoms/signs of progressive sensory-motor deficit in the lower limbs); patient expertise, clinical expertise, research and pathways. Uniquely, the toolkit drew upon the lived experiences of patients suffering from CES to inform the content.


Difficulties with being socially accepted: An experimental study in borderline personality disorder.
Anxious preoccupation with real or imagined abandonment is a key feature of borderline personality disorder (BPD). Recent experimental research suggests that patients with BPD do not simply show emotional overreactivity to rejection. Instead, they experience reduced connectedness with others in situations of social inclusion. Resulting consequences of these features on social behavior are not investigated yet. The aim of the present study was to investigate the differential impact of social acceptance and rejection on social expectations and subsequent social behavior in BPD. To this end, we developed the Mannheim Virtual Group Interaction Paradigm in which participants interacted with a group of computer-controlled avatars. They were led to believe that these represented real human coplayers. During these interactions, participants introduced themselves, evaluated their coplayers, assessed their social expectations and received feedback signaling either acceptance or rejection by the alleged other participants. Subsequently, participants played a modified trust game, which measured cooperative and aggressive behavior. Fifty-six nonmedicated BPD patients and 56 healthy control participants were randomly and double-blindly assigned to either the group-acceptance or group-rejection condition. BPD patients showed lower initial expectations of being socially accepted than healthy controls. After repeated presentation of social feedback, they adjusted their expectations in response to negative, but not to positive feedback. After the experience of social acceptance, BPD patients behaved less cooperatively. These experimental findings point to a clinically relevant issue in BPD: Altered cognitive and behavioral responses to social acceptance may hamper the forming of stable cooperative relationships and negatively affect future interpersonal relationships. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Planning breast reconstruction with deep inferior epigastric artery perforating vessels: multidetector CT angiography versus color Doppler US.
To evaluate the accuracy of multidetector computed tomographic (CT) angiography versus color Doppler ultrasonography (US) for perforating artery identification, intramuscular course of perforator vessel assessment, and superficial venous communication detection before a deep inferior epigastric perforator (DIEP) procedure for breast reconstruction. Informed consent and institutional review board approval were obtained. Forty-five patients underwent multidetector CT angiography and color Doppler US to identify the DIEP vessel prior to breast reconstruction surgery. Findings at surgery were used as a reference for accuracy evaluations. The accuracy for identifying dominant perforator arteries was 97% for color Doppler US and 91% for CT angiography. Perforator arteries suitable for surgery were identified in 90% of cases with color Doppler US and in 95% of cases with CT angiography. For measurement of perforator calibers, surgical findings were similar to color Doppler US measurements (P = .33) but were significantly different than CT measurements (P < .0001). The accuracies for intramuscular course of perforator vessel assessment and superficial venous communication detection were 95% and 97% for CT and 84% and 80% for color Doppler US, respectively. In our population, the absence of superficial venous communication was associated with a risk for flap morbidity (P = .009). Both color Doppler US and CT angiography resulted in accurate DIEP mapping. Color Doppler US was superior for measuring perforator artery calibers, and CT angiography was superior for estimating the intramuscular course of the perforator vessel and identifying superficial venous communications. Considering x-ray exposure and results of this study, employing multidetector CT angiography is suggested only in selected cases.


Using neural networks to solve the multicast routing problem in packet radio networks.
The primary function of a packet radio network is the efficient transfer of information between source and destination nodes using minimal bandwidth and end-to-end delay. Many researchers have investigated the problem of minimizing the end-to-end delay from a single source to a single destination for a variety of networks; however, very little work is reported about routing mechanisms for the common case where a particular information packet is intended to be sent to more than one destination in the network. This is known as multicasting. A simplified version of the problem is to ignore the packet delay at each node, then the problem becomes one of finding solutions which require the least number of transmissions. Determination of an optimal solution is NP-complete meaning that suboptimal solutions are frequently tolerated. The problem becomes more rigorous if packet delays are included in the network topology. This paper describes a practical technique for the computation of optimum or near optimum solutions to the multicasting problem with and without packet delay. The method is based on the Hopfield neural network and experiment has shown this method to yield near optimal solutions while requiring a minimum of CPU time.


Coatings for biodegradable magnesium-based supports for therapy of vascular disease: A general view.
Metal stents are used as base material for fabrication of medical devices to support and improve the quality of life of patients with cardiovascular diseases such as arterial stenoses. Permanently present implants may induce responses that resemble adverse wound healing that compromise tissue function. A similar process namely restenosis, frequently may occur after the use of this kind of implants. However, the use of non-permanent, resorbable stents are a promising option to avoid this problem. The advantage of these implants is that they can degraded upon vascular repair. The most common metal used for this application, is magnesium (Mg) which is an interesting material due its biological properties and because it is an essential element for human life. However, Mg-based resorbable biomaterial have some restrictions in clinical applications because its corrosion resistance, and mechanical properties. As solutions of this problem, the material can be modified in its composition (Mg-based alloys) or by surface treatments. This review shows and discusses recent challenges in the improvement of Mg-based biomaterials to be used to treat vascular disease and novel approaches at design-based biomaterials engineering of the same. Design-based methodologies are introduced and discussed in the context of balancing multi-functional properties against adaptation to the complex extreme in vivo environment. Traditional alloying approaches of Mg-based biomaterials are also discussed in the context of corrosion resistance controlled by surface modification strategies including conversion techniques: physicochemical or electrochemical transformation such as anodization, plasma and electrophoretic deposition.


Somatic experiencing: using interoception and proprioception as core elements of trauma therapy.
Here we present a theory of human trauma and chronic stress, based on the practice of Somatic Experiencing(®) (SE), a form of trauma therapy that emphasizes guiding the client's attention to interoceptive, kinesthetic, and proprioceptive experience. SE™ claims that this style of inner attention, in addition to the use of kinesthetic and interoceptive imagery, can lead to the resolution of symptoms resulting from chronic and traumatic stress. This is accomplished through the completion of thwarted, biologically based, self-protective and defensive responses, and the discharge and regulation of excess autonomic arousal. We present this theory through a composite case study of SE treatment; based on this example, we offer a possible neurophysiological rationale for the mechanisms involved, including a theory of trauma and chronic stress as a functional dysregulation of the complex dynamical system formed by the subcortical autonomic, limbic, motor and arousal systems, which we term the core response network (CRN). We demonstrate how the methods of SE help restore functionality to the CRN, and we emphasize the importance of taking into account the instinctive, bodily based protective reactions when dealing with stress and trauma, as well as the effectiveness of using attention to interoceptive, proprioceptive and kinesthetic sensation as a therapeutic tool. Finally, we point out that SE and similar somatic approaches offer a supplement to cognitive and exposure therapies, and that mechanisms similar to those discussed in the paper may also be involved in the benefits of meditation and other somatic practices.


Single-phase dual-energy CT allows for characterization of renal masses as benign or malignant.
To evaluate the diagnostic accuracy of dual-energy CT (DECT) in renal mass characterization using a single-phase acquisition. A total of 202 patients (148 males, 54 females; 63 +/- 13 years) with ultrasound-based suspicion of a renal mass underwent unenhanced single energy and nephrographic phase DECT on a dual source scanner (Siemens Somatom Definition Dual Source, n = 174; Somatom Definition Flash, n = 28). Scan parameters for DECT were: tube potential, 80/100 and 100/Sn140 kVp; exposure, 404/300 and 96/232 effective mAs; collimation, 14 x 1.2/32 x 0.6 mm. Two abdominal radiologists assessed DECT and SECT image quality and noise on a 5-point visual analogue scale. Using solely the DE acquisition including virtual nonenhanced (VNE) and color coded iodine images that enable direct visualization of iodine, masses were characterized as benign or malignant. In a second reading session after 34 to 72 (average: 55) days, the same assessment was again performed using both the true nonenhanced (TNE) and nephrographic phase scans thereby simulating conventional single-energy CT. Sensitivities, specificities, diagnostic accuracies, and interpretation times and were recorded for both reading paradigms. Dose reduction of a single-phase over a dual-phase protocol was calculated. Results were tested for statistical significance using the paired Wilcoxon signed rank test and student t test. Differences in sensitivities were tested for significance using the McNemar test. Of the 202 patients, 115 (56.9%) underwent surgical resection of renal masses. Histopathology showed malignancy in 99 and benign tumors in 18 patients, in 48 patients (23.7%), follow-up imaging showed size stability of lesions diagnosed as benign, and 37 patients (18.3%) had no mass. Based on DECT only, 95/99 (96.0%) patients with malignancy and 96/103 (93.2%) patients without malignancy were correctly identified, for an overall accuracy of 94.6%. The dual-phase approach identified 96/99 (97.0%) and 98/103 (95.1%), accuracy 96.0%, P > 0.05 for both. Mean interpretation time was 2.2 +/- 0.8 minutes for DECT, and 3.5 +/- 1.0 minutes for the dual-phase protocol, P < 0.001. Mean VNE/TNE image quality was 1.68 +/- 0.65/1.30 +/- 0.59, noise was 2.03 +/- 0.57/1.18 +/- 0.29, P < 0.001 for both. Omission of the true unenhanced phase lead to a 48.9 +/- 7.0% dose reduction. DECT allows for fast and accurate characterization of renal masses in a single-phase acquisition. Interpretation of color coded images significantly reduces interpretation time. Omission of a nonenhanced acquisition can reduce radiation exposure by almost 50%.


Optimising exercise training in peripheral arterial disease.
Peripheral arterial disease (PAD) is an obstructive condition where the flow of blood through peripheral arteries is impeded. During periods of increased oxygen demand (e.g. during exercise), peripheral limb ischaemia occurs, resulting in the sensation of muscle pain termed 'claudication'. As a result of claudication, subjects' ability to exercise is greatly reduced affecting their quality of life. Although many treatment options for patients with PAD exist, exercise training is an effective and low-cost means of improving functional ability and quality of life. Currently, there are limited specific recommendations to assist the exercise prescription and programming of these individuals. This review summarises data from 28 exercise training studies conducted in patients with PAD and formulates recommendations based on their results. Exercise training for patients with PAD should involve three training sessions per week comprising 45 minutes of intermittent treadmill walking in a supervised environment for a time period of 20 weeks or more. Encouragement and direction is given to further research aimed at investigating the effectiveness of training programmes in these patients.


A bottlenose dolphin discriminates visual stimuli differing in numerosity.
A bottlenose dolphin was trained to discriminate two simultaneously presented stimuli differing in numerosity (defined by the number of constituent elements). After responding correctly to stimuli consisting of three-dimensional objects, the dolphin transferred to two-dimensional stimuli. Initially, a variety of stimulus parameters covaried with the numerosity feature. By systematically controlling for these stimulus parameters, it was demonstrated that some of these attributes, such as element configuration and overall brightness, affected the animal's discrimination performance. However, after all the confounding parameters were under control, the dolphin was able to discriminate the stimuli exclusively on the basis of the numerosity feature. The animal then achieved a successful transfer to novel numerosities, both intervening numerosities and numerosities outside the former range. These findings provide substantial evidence that the dolphin could base his behavior on the numerosity of a set independently of its other attributes and that he represented ordinal relations among numerosities.


Treatment of herpes simplex keratitis with idoxuridine and vidarabine: a double-blind study.
A double controlled clinical study comparing idoxuridine (IDU) and vidarabine (ara-A) in the treatment of uncomplicated herpes simplex keratitis was carried out with 10 patients. No statistically significant differences occurred in the healing time between IDU (6.8 days) and ara-A (8.0 days). Two moderately adverse reactions to IDU were observed, but no demonstrable ocular toxicity was noted with ara-A.


Role of extracellular matrix in regulation of staurosporine-induced apoptosis in breast cancer cells.
Autocrine and paracrine mechanisms modulate the synthesis and secretion of extracellular matrix (ECM); moreover, each component of the ECM is capable of modulating the synthesis and release of other ECM molecules. Therefore, the synthesis of ECM glycoprotein fibronectin and laminin was studied in the human breast cancer cell lines MCF7 and MDA MB 23, plated on different ECM. Our results showed that the cells plated on a fibronectin substrate increased laminin synthesis: this event correlated with an increase in alpha2 and alpha3 integrin subunits. Staurosporine-induced apoptosis was then analyzed in the cell lines plated on different ECM. Staurosporine treatment determined the apoptosis of 35 and 33% respectively of MDA MB 231 and MCF7; these values increased to 60 and 64% in cells plated on laminin, to 48 and 63% in cells plated on fibronectin and to 64 and 69% in cells plated on matrigel. Moreover, staurosporine treatment decreased bcl-2 expression in the cells plated on fibronectin and laminin. Yet, staurosporine treatment determined PARP cleavage and PARP partial disappearance when the cells were plated on matrigel. Finally, a partial loss of function mutant Ras protein that activated only Raf pathway, was expressed in MCF7, in order to identify whether the increase of apoptosis induced by extracellular matrix involved the Raf/MAP kinase pathway. The increase of apoptosis of the cells plated on matrigel suggested that the activation of the Raf pathway is probably involved in the decrease of survival on matrigel. These data demonstrate that the modification of ECM modulates the apoptotic process of breast cancer cells and suggest that it is worthwhile to dissect the role of ECM in the control of apoptotic process.


The MYB59 transcription factor negatively regulates salicylic acid- and jasmonic acid-mediated leaf senescence.
Leaf senescence is the final stage of leaf development and is affected by various exogenous and endogenous factors. Transcriptional regulation is essential for leaf senescence, however, the underlying molecular mechanisms remain largely unclear. In this study, we report that the transcription factor MYB59, which was predominantly expressed in early senescent rosette leaves, negatively regulates leaf senescence in Arabidopsis (Arabidopsis thaliana). RNA sequencing revealed a large number of differentially expressed genes involved in several senescence-related biological processes in myb59-1 rosette leaves. Chromatin immunoprecipitation and transient dual-luciferase reporter assays demonstrated that MYB59 directly repressed the expression of SENESCENCE ASSOCIATED GENE 18 and indirectly inhibited the expression of several other senescence-associated genes to delay leaf senescence. Moreover, MYB59 was induced by salicylic acid (SA) and jasmonic acid (JA). MYB59 inhibited SA production by directly repressing the expression of ISOCHORISMATE SYNTHASE 1 and PHENYLALANINE AMMONIA-LYASE 2 and restrained JA biosynthesis by directly suppressing the expression of LIPOXYGENASE 2, thus forming two negative feedback regulatory loops with SA and JA and ultimately delaying leaf senescence. These results help us understand the novel function of MYB59 and provide insights into the regulatory network controlling leaf senescence in Arabidopsis.


Attentional Bias and Training in Social Anxiety Disorder.
Cognitive behavioral therapy (CBT) is one of the most effective treatment modalities for social anxiety disorder (SAD), showing a high level of clinical evidence supporting its effectiveness. On the other hand, lack of the desired benefit from this treatment in some patients causes continuation of the search for new techniques. Recent research studies have focused on attentional bias and attention training in SAD. Attention processes in SAD have been a major target of interest and investigation since the introduction of the first cognitive models explaining SAD. In the first model, it was highlighted that attention was self-focused. The relationship between threatening stimuli and attention was considered in the subsequent models. Attentional bias towards threat may take place in several ways, such as facilitated processing of threat, difficulty in disengaging attention from the threat and avoidance of attention from the threat. After these descriptions regarding the phenomenology of the disorder, treatments to modify attention, processes were developed. In spite of conflicting results, investigations on attentional training are promising. Attention processes, attentional bias and attentional training in SAD are discussed in this review.


Axial spondyloarthritis classification criteria: the debate continues.
The Assessment of Spondyloarthritis International Society (ASAS) axial spondyloarthritis (axSpA) classification criteria marked a major step forward in SpA research, distinguishing axial from peripheral disease, and allowing earlier identification through MRI. This facilitated all aspects of research including epidemiology, therapeutics and patient outcomes. The ASAS axSpA classification criteria have been applied broadly in research, and were validated in a recent meta-analysis of international studies. Concerns arose because of clinical differences between the clinical and imaging arms, which imply different risk for radiographic progression, and perform differently in validation studies. Low specificity of the MRI finding of sacroiliac joint bone marrow edema may lead to misclassification in populations with low axSpA prevalence. We suggest methodology to improve upon the criteria, including rigorous assessment of potential candidate criteria sets, discrete choice experiments to allow consideration of feature weights, and validation. Separately, assessment of structural and inflammatory MRI abnormalities should be performed to refine the MRI definition of sacroiliitis. The debate regarding the validation and modification of the ASAS axSpA classification criteria should lead to international efforts to build upon the gains made by these criteria, to further refine the axSpA population definitions for research and ultimately improve patient outcomes.


Effect of human recreation on bird anti-predatory response.
Wildlife perceive humans as predators, and therefore normally flushes. Flight initiation distance (FID) is the distance a human can approach an animal at a steady pace until it flushes. Recently, several studies showed differences in within-species FID according to human presence by comparing urban and rural habitats, with urban birds showing reduced FIDs. However, urban and rural habitats also differ in structure, which might affect FID. Therefore, in order to understand the real effect of human presence, we investigated whether differences in FID are also present in natural habitats (forests), differing only in the intensity of human use for recreation. We found that human frequentation had a distinct effect on bird escape responses, with shorter FIDs in forests more-heavily frequented by humans than in forests rarely visited by humans. Whether this finding is driven by non-random spatial distribution of personalities (shy vs. bold) or phenotypic plasticity (habituation to humans) cannot be assessed with our data. Studies relying on FIDs should also incorporate human recreation intensity, as this affects the measurements strongly.


Epidemiology of Lyme disease among workers of forest inspectorates in Poland.
Lyme disease (Lyme borreliosis, LB) is a systemic tick-borne disease. Its symptoms include dermatological changes and systemic manifestations such as musculoskeletal, neurologic, and cardiac. The etiologic agent of LB is a spirochete known as Borrelia burgdorferi (B.b.) with rodents and small mammals as its animal reservoir. In Poland, there are approximately 9-10 cases of the disease per 100,000 inhabitants each year. Analyis of the incidence of Lyme borreliosis and the clinical picture of the disease among foresters. The research material consisted of data collected in a diagnostic survey conducted by use of a survey questionnaire method. The study involved 100 randomly selected workers of the forest inspectorate in Podkarpackie Voivodeship. Group I consisted of men between 30-45 years old with an average length of service of 14 years (48%); group II consisted of men between 45-55 years old with an average length of service of 24 years (52%). Only 25% of the foresters from the first group, younger in age and with shorter service, had never been bitten by a tick, while 60% were bitten once, and 15% had been repeatedly bitten. In the second group, older in age and with longer service, only 3% had never been bitten by a tick, 35% were bitten once, while 62% had been repeatedly bitten. LB was diagnosed in 30% of the research participants from the first group and in 45% from the second group. Most frequently, LB was diagnosed as a result of the presence of erythema migrans (55%), ELISA test (20%), and Western Blot test (22%). The most frequent symptoms among the participants were: erythema migrans (45%), fever and shivers (35%), muscle pain and cramps (15%), other symptoms (5%). Permanent presence of symptoms was reported by 70% of the participants, 25% experienced symptoms periodically, and 5% only sporadically. LB occurs more frequently among foresters older in age and with longer service (45%); in the younger group--30%. Despite knowledge on preventive methods, there is no effective preventive method for this disease.


Proteome analysis of human arterial tissue discloses associations between the vascular content of small leucine-rich repeat proteoglycans and pulse wave velocity.
We hypothesized that arterial stiffness is associated with changes in the arterial protein profile, particularly of extracellular matrix components. We aimed at determining differentially expressed proteins by quantitative proteome analysis in arterial tissue from patients with different degrees of arterial stiffness. Arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV), central blood pressure and augmentation index by pulse wave analysis were measured the day before surgery in a group of patients undergoing coronary artery bypass grafting. Protein extracts of well-defined, homogenous, nonatherosclerotic individual samples of the left mammary artery from 10 of these patients with high PWV and 9 with low PWV were compared by quantitative proteome analysis, using tandem mass tag labeling and nano-liquid chromatography mass spectrometry/mass spectrometry. Of 418 quantified proteins, 28 were differentially expressed between the groups with high and low PWV (P<0.05). Three of 7 members of the extracellular matrix family of small leucine-rich repeat proteoglycans displayed significant differences between the 2 groups (P=0.0079; Fisher exact test). Three other ECM proteins were differentially regulated, that is, collagen, type VIII, α-1 and α-2 and collagen, type IV, α-1. Several proteins related to smooth muscle cell function and structure were also found in different amounts between the 2 groups. Changes in the arterial amounts of small leucine-rich proteoglycans, known to be involved in collagen fibrillogenesis, and of some nonfibrillar collagens in combination with alterations in proteins related to functions of the human arterial smooth muscle are associated with arterial stiffness, as determined by PWV.


[Inhaled corticosteroids and wheezing post-bronchiolitis].
To determine whether inhaled corticosteroid therapy given for 3 months after mild bronchiolitis decreases the incidence and/or severity of wheezing in the following 12 months. Multicentric, single-blind, controlled, randomised intervention study. Primary Health Care Centers in Lezo, Beraun, Andoain and Irún (Gipuzkoa, Spain). Infants less than 12 months old (n = 94) diagnosed with mild bronchiolitis. We established two groups of patients: group 1 (n = 47) was treated with inhaled beclomethasone (250 pg/12 hours) using a valved holding chamber (Babyhaler); the treatment started eight days after diagnosis of bronchiolitis and lasted 3 months. Group 2 (n = 47) received no treatment. We compared the number of wheezing episodes and their severity during the intervention period (3 months) and the follow-up period (12 months) with the Students t-test and the Chi-squared test. We studied 89 infants (group 1, n = 42; group 2, n = 47), 67% of whom wheezed during the study period (15 months). There were no significant differences between the treatment and the control group in the study periods. Inhaled beclomethasone given for 3 months does not significantly modify the occurrence of wheezing episodes during the treatment period or during the following 12 months.


Assessing community needs. A system's six-step approach yields tangible results.
To respond to the changing needs of the communities it serves, the Sisters of Mercy Health System-St. Louis (SMHS) is committed to implementing and advocating for innovative health and social services that improve the health and quality of life of communities the system serves. One means to achieve these ends is the Agenda for Social Accountability. As part of this agenda, each of the system's strategic service units (SSUs) performs a community needs assessment. Phase one of the assessment consists of six steps: 1. Assign administrative responsibility 2. Review available data 3. Obtain information on community health status 4. Interview community leaders 5. Summarize results in a draft report 6. Incorporate conclusions into the strategic plan Many of the system's SSUs have completed the first cycle of the social accountability agenda and are exploring new initiatives for phase two. SMHS is investigating the idea of assessing the functional status of representative samples of community members as another method of measuring health status. And its primary research is broadening to include written surveys and focus groups with select audiences.


Fibroblast growth factor-2 regulates the synthesis of hyaluronan by human periodontal ligament cells.
Basic fibroblast growth factor (FGF-2) can enhance biological potentials of periodontal ligament cells and its topical application induces considerable periodontal tissue regeneration in vivo. In this study, we examined the effect of FGF-2 on the production of hyaluronan (HA), an extracellular matrix playing important roles in homeostasis and inflammatory/wound healing responses, by human periodontal ligament (HPDL) cells. An inhibition binding-protein assay revealed that FGF-2 significantly increased HA production by HPDL cells in a dose dependent manner. Analysis by HPLC revealed that in conditioned medium of FGF-2-treated HPDL cells HA had a higher molecular mass, compared to that of untreated HPDL cells. RT-PCR analysis revealed the enhancement of mRNA expression of hyaluronan synthase (HAS) 1 and HAS 2, both of which contribute to the production of HA with a high molecular mass, but not HAS 3 in the FGF-2-treated HPDL cells. In contrast, three isoforms of hyaluronidase (HYAL) transcript were unchanged in the FGF-2-treated HPDL cells. These results provide new evidence for the possible involvement of FGF-2 in the regulation of HA production and its appreciable roles in not only homeostasis but also regeneration of periodontal tissues.


Nutritional supplements for pregnant and lactating bitches.
This review covers the use of common nutritional supplements for the bitch and puppies. Basic nutrients, including fat, protein, minerals, vitamins and essential fatty acid supplementation, will be discussed. Newer supplements, such as probiotics for stimulation of the immune system of the bitch and puppy, and for the non-pharmaceutical treatment of weaning diarrhea, will also be covered.


Personality typology in relation to muscle strength.
Physical inactivity plays a central role in the age-related decline in muscle strength, an important component in the process leading to disability. Personality, a significant determinant of health behaviors including physical activity, could therefore impact muscle strength throughout adulthood and affect the rate of muscle strength decline with aging. Personality typologies combining "high neuroticism" (N ≥ 55), "low extraversion" (E < 45), and "low conscientiousness" (C < 45) have been associated with multiple risky health behaviors but have not been investigated with regards to muscle strength. The purpose of this study is to investigate associations between individual and combined typologies consisting of high N, low E, and low C and muscle strength, and whether physical activity and body mass index act as mediators. This cross-sectional study includes 1,220 participants from the Baltimore Longitudinal Study of Aging. High N was found among 18%, low E among 31%, and low C among 26% of the sample. High levels of N, particularly when combined with either low E or low C, were associated with lower muscle strength compared with having only one or none of these personality types. Facet analyses suggest an important role for the N components of depression and hostility. Physical activity level appears to partly explain some of these associations. Findings provide support for the notion that the typological approach to personality may be useful in identifying specific personality types at risk of low muscle strength and offer the possibility for more targeted prevention and intervention programs.


Rapid quantitative bioassay of osteoinduction.
We developed a reproducible, relatively rapid bioassay that quantitatively correlates with the osteoinductive capacity of demineralized bone matrix obtained from human long bones. We have found that Saos human osteosarcoma cells proliferate in response to incubation with demineralized bone matrix and that an index of this proliferative activity correlates with demineralized bone matrix-induced osteogenesis in vivo. The bioassay (Saos cell proliferation) had an interassay coefficient of variation of 23 +/- 2% and an intra-assay coefficient of 11 +/- 1%. Cell proliferation was normalized to a standard sample of demineralized bone matrix with a clinically high osteoinductive capacity, which was assigned a value of one. The Saos cell proliferation for each sample was related to the standard and assigned a value placing it into the low (0.00-0.39), intermediate (0.40-0.69), or high (0.70-1.49) osteoinductive index group. Osteoinduction of human demineralized bone matrix was quantitated by expressing new bone formation as a function of the total bone volume (new bone plus the demineralized bone powder). The demineralized bone matrix was placed in pouches formed in the rectus abdominis muscles of athymic rats, and endochondral bone formation was assessed at 35 days following implantation, when marrow spaces in the ossicles were formed by new bone bridging the spaces between demineralized bone matrix particles. The proliferative index correlated with the area of new bone formation in histological sections of the newly formed ossicles. When the proliferative index (the osteoinductive index) was divided into low, intermediate, and high groups, the correlation between it and new bone formation (osteoinduction) was 0.850 (p < 0.0005) in 25 samples of demineralized bone matrix. There was no overlap in the osteoinduction stimulated between the samples with low and high osteoinductive indices. We conclude that the proliferation assay is useful for the routine screening of bone allograft donors for osteoinductive potential. Furthermore, the two-dimensional area of new bone formation, as it relates to total new bone area, is a quantitative measure of osteoinduction.


Identification and characterization of incomplete hepatitis A virus particles.
The range of hepatitis A virus (HAV) particles generated during persistent infection of different cell lines was studied. Buoyant density and sedimentation analyses of cell extracts revealed a uniform profile of particles in all cell lines analysed except for BS-C-1 cells. The virion itself usually represented less than 50% of the total mass of virus antigen. A major portion of the antigen was associated with non-infectious, empty particles, which banded at 1.305 g/ml and 1.20 g/ml CsCl, and sedimented in sucrose gradients at 76S and 59S. Empty HAV particles were similar to those of poliovirus with respect to their physical stability and had the characteristic capsid protein content (VP0, VP1 and VP3). An additional RNA-containing particle, probably the provirion, represented only a minor species characterized by a buoyant density of 1.32 g/ml in CsCl and sedimenting at 130S.


[Possibilities and expectations of hybridoma technology: national and international response].
The application of monoclonal antibodies has become a great commercial success. It is interesting to know the factors that have contributed to this. A few years ago a case study was published--financed by the EEC--in which various factors were studied. This study is briefly discussed. The Dutch government has identified hybridoma technology as important for Dutch industry and is attempting to stimulate the research effort by making innovation funds in the area of biotechnology available. The various possibilities that have been created are discussed. Finally, attention is given to development in the area of computerized hybridoma data banks. Some conclusions and recommendations are given.


Influence of Pair-housing on Sleep Parameters Evaluated with Actigraphy in Female Rhesus Monkeys.
Rhesus monkeys are naturally social animals, and behavioral management strategies have focused on promoting pairhousing in laboratory settings as an alternative to individual or group housing. In humans, co-sleeping can have a major impact on bed partners' sleep, raising the possibility that pair-housing also may influence sleep parameters in monkeys. In the present study, we investigated if pair-housing would impact home-cage partner's sleep in female rhesus monkeys, and if nighttime separation using socialization panels would alter this pattern. Sleep parameters of 10 experimentally naïve adult female rhesus monkeys (5 pairs) were evaluated for 7 consecutive days using actigraphy monitors attached to primate collars. Paired animals then were separated by socialization panels during the night, and sleep-associated measures were evaluated for 7 consecutive days. The data showed that sleep efficiency was significantly lower when monkeys were pairhoused as compared with when they were separated. On the nights when subjects were pair-housed, a positive correlation was detected for sleep measures (both sleep latency and efficiency) of both members of a pair (R2's = 0.16-0.5), suggesting that pair-housing influences sleep quality. On nights when subjects were separated, no correlations were observed for sleep measures between members of the pairs (R2's = 0.004-0.01), suggesting that when separated, the home-cage partner's sleep no longer influenced the partner's sleep. Our results indicate that pair-housing has a strong impact on the home-cage partner's sleep, and that this pattern can be prevented by nighttime separation using socialization panels. Studies evaluating sleep in pair-housed monkeys should consider the effects that the partner's sleep may have on the subject's sleep. Sleep is a biologic phenomenon and experimental outcome that affects physical and behavioral health and altered sleep due to pair-housing may affect a range of research outcomes.


Periorbital and orbital cellulitis: a 10-year review of hospitalized children.
Periorbital cellulitis is often difficult to distinguish from orbital cellulitis, which is a potentially lethal infection involving the contents of the orbit. A delay in diagnosis and appropriate treatment may result in serious complications. We studied the predisposing factors, microbiologic data, clinical features, complications, and treatment of periorbital and orbital cellulitis in childhood. Eighty-three medical records of patients (mean age 3.7 ± 3.1 years) admitted to the Department of Pediatrics with a diagnosis of periorbital or orbital cellulitis during the 10-year period January 1997 to December 2007 were retrospectively studied. In this series, periorbital cellulitis occurred more frequently (83%) than orbital cellulitis (17%). Of the children with periorbital cellulitis, 85% were younger than 5 years of age, while 62% of the children with orbital cellulitis were older than 5 years of age. The most common predisposing factors in periorbital cellulitis were upper respiratory infection (68%) and trauma to the eyelids (20%), while sinusitis was more frequently associated with orbital cellulitis (79%). Blood and skin cultures were usually negative. The most common isolated pathogens were Staphylococcus aureus, Streptococcus pneumoniae, and Staphylococcus epidermidis. Forty-five of the 83 children were treated with intravenous ceftriaxone + clindamycin (mean duration 8.6 ± 5.5 days). Intravenous antibiotics alone was an effective management in most of the patients, but a small proportion (6%) required surgical intervention. Upper respiratory infection and sinusitis are the most important predisposing factors for periocular infection. Streptococcus species are the predominant causative agents. Both diseases can usually be successfully treated with intravenous antibiotics, but some patients may require surgery to control extensive infection.


Infant mouse as a sensitive bioassay system for carcinogenicity of N-nitroso compounds.
Five groups of 48, C57BLxC3H F1, male mice, 15 days old, were administered NDEA intraperitoneally at the following levels: 0.0 (saline only), 0.625, 1.25, 2.50 and 5.00 microgram per g body weight, in a single dose. Groups of eight mice from each of the dose levels were killed at 40, 50, 60, 70, 80 and 90 weeks of age. The nodular liver lesions were classified s (a) focal areas of non-specific cellular changes, (b) hyperplastic nodules, (c) hepatocellular adenomas and (d) hepatocellular carcinomas. Regardless of the dose, all the animals developed hepatocellular carcinomas. The average latent periods, however, were inversely proportional to dose, being 66 weeks with the lowest dose and 44 weeks with the highest dose. The multiplicity and the average weight of the early nodular lesions (50 weeks) was directly related to th NDEA dose. Thus the higher multiplicity was associated with faster emergence of hepatocellular carcinomas. The high susceptibility to hepatocellular carcinogenesis, in association with the short latency, makes the infant mouse a sensitive bioassay system for assessing the carcinogenic potential of N-nitroso compounds.


Endovascular treatment of unusual multiple aneurysms of the internal carotid artery-posterior communicating artery complex--case report.
A 79-year-old female presented with subarachnoid hemorrhage due to rupture of a rare true posterior communicating artery (PCoA) aneurysm and with poor general condition. Endovascular therapy was performed in the chronic stage. Right carotid angiography just before embolization demonstrated unusual multiple aneurysms of the internal carotid artery (ICA)-PCoA complex. Superselective angiography and aneurysmography using microcatheter revealed two separate aneurysms arising from the PCoA and the ICA-PCoA junction. Endovacular embolization using Guglielmi detachable coils (GDCs) was successfully performed for both aneurysms and complete occlusions were achieved with the PCoA fully patent. Embolization with GDCs is a good alternative to surgical clipping for PCoA aneurysm after careful evaluation of superselective angiography.


Therapeutic hypothermia for the management of intracranial hypertension in severe traumatic brain injury: a systematic review.
Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. Raised Intracranial pressure (ICP) is an important predictor of mortality in patients with severe TBI and aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome. The acute post-injury period in TBI is characterized by several pathophysiologic processes that start in the minutes to hours following injury. All of these processes are temperature-dependent; they are all aggravated by fever and inhibited by hypothermia. This study reviewed the current clinical evidence in support of the use of therapeutic hypothermia (TH) for the treatment of intracranial hypertension (ICH) in patients with severe TBI. This study identified a total of 18 studies involving hypothermia for control of ICP; 13 were randomized controlled trials (RCT) and five were observational studies. TH (32-34°C) was effective in controlling ICH in all studies. In the 13 RCT, ICP in the TH group was always significantly lower than ICP in the normothermia group. In the five observational studies, ICP during TH was always significantly lower than prior to inducing TH. Pending results from large multi-centre studies evaluating the effect of TH on ICH and outcome, TH should be included as a therapeutic option to control ICP in patients with severe TBI.


Potential roles of antisense therapy in the molecular targeting of genes involved in cancer (review).
Recent advances in antisense methods targeting genes involved in cell proliferation, angiogenesis, and apoptosis provide a potential anticancer effect alone as well as in combination with drugs, and antisense therapy may be useful in overcoming drug resistance and increasing survival in patients with advanced cancer including those with solid tumors. In particular, antisense to Bcl-2 comprises a most promising therapy and is being tested in combination with anticancer drugs in randomized phase III trials for chronic lymphocytic leukemia, multiple myeloma, and malignant melanoma. The targeting of apoptosis-related proteins is promising for enhancing the effect of cancer chemotherapy. The molecular mechanism by which anticancer drugs induce apoptosis has been identified as mitochondrial dysfunction mediated by the release of cytochrome c. Modulation of multiple antiapoptotic signaling pathways involving Bcl-2 and Akt, which are related to growth factor-stimulated signal transduction in cell survival, is essential for enhancement of the cytotoxic effect of anticancer drugs. Herein, we review the current status of antisense therapy and its potential for enhancing anticancer drug-induced apoptosis.


Effects of hyperthyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat.
1. The effects of hyperthyroidism on the sensitivity and responsiveness of glycolysis and glycogen synthesis to insulin were investigated in the isolated incubated soleus muscle of the rat. 2. Hyperthyroidism, which was induced by administration of tri-iodothyronine (T3) to rats for 2, 5 or 10 days, increased fasting plasma concentrations of glucose, insulin and free fatty acids. 3. Administration of T3 for 2 or 5 days increased the rates of glycolysis at all insulin concentrations studied: this was due to increased rates of both glucose phosphorylation and glycogen breakdown, but there was no effect of T3 on the sensitivity of glycolysis to insulin. However, administration of T3 for 10 days increased the sensitivity of the rate of glycolysis to insulin. 4. The concentration of adenosine in the gastrocnemius muscles of the rats was not different from controls after 5 days, but it was markedly decreased after 10 days of T3 administration. If these changes are indicative of changes in the soleus muscle, the increased sensitivity of glycolysis to insulin found after 10 days' T3 administration could be due to the decrease in the concentration of adenosine. 5. Administration of T3 decreased the sensitivity of glycogen synthesis to insulin and the glycogen content of the soleus muscles. This may explain the decreased rates of non-oxidative glucose disposal found in spontaneous and experimental hyperthyroidism in man. 6. The rates of glucose oxidation did not change after 2 days, but they were increased after 5 and 10 days of T3 administration.


Randomized controlled pilot trial of a hand-held patient-oriented, insulin regimen optimizer.
A robust, hand-held, patient-oriented insulin regimen optimizer (POIRO) has been developed. Relevant information is entered by selecting appropriate items from choices displayed on a touch-sensitive screen rather than a conventional keyboard. All data items are recorded, together with their time and date of entry, and may be recalled at any time with glucose values displayed graphically to provide an overview of glycaemic control. When requested, an integral, hybrid, statistical and rule-based expert system program uses all available data to suggest an optimum insulin dose within physician determined, pre-set limits. POIRO has been formally evaluated in a randomized crossover pilot trial, comparing two 3 week periods with and without decision support, in six patients with type 1 diabetes. Mean (SE) pre-prandial blood glucose levels were significantly lower during the period when decision support was available (7.5 (0.4) versus 8.9 (0.4) mmol/l, p = 0.015) with no increase in the frequency or severity of hypoglycaemia. The device, which was well received by the patients, may offer a relatively inexpensive method of providing expert diabetic advice at a distance. The persistence of improved glycaemic control, even after decision support was switched off, suggests the device could be used intermittently by patients and may have educational value.


Changes in multiple cytokine concentrations in the aqueous humour of neovascular age-related macular degeneration after 2 months of ranibizumab therapy.
To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). This prospective study included 48 treatment-naïve neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected ~0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p<0.0001), and MMP-9, 0.92 and 1.5 (p=0.0216), respectively. Concentrations of all cytokines decreased significantly after two consecutive ranibizumab injections, except for MMP-9, which increased significantly. After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased.


Feasibility and diagnostic accuracy of teledermatology in Swiss primary care: process analysis of a randomized controlled trial.
To test feasibility and diagnostic accuracy of dermatologist's feedback based on digital images of skin lesions collected in Swiss primary care. This was a process analysis of a randomized controlled trial, conducted in 2011/2012. 30 of 78 general practitioners (GPs) were randomized to an intervention, which included dermatologist's feedback on digital images of skin lesions. Feedback was categorized into four categories: (1) no further investigation; (2) clinical observation; (3) biopsy; and (4) other. Histologic findings were allocated to the same categories. Feasibility was measured in the perspective of GPs concerning technical handling and of dermatologists as proportion of images usable for feedback. Diagnostic accuracy was measured as proportion of malignant histology of the first three feedback groups. No long-term data was collected. 981 images of skin lesions were collected, two were not eligible due to low quality of images. The majority of GPs (77.8%) reported no problem with the procedure. 207 images were in feedback category 1, 353 in 2, 360 in 3 and 59 in 4. A total of 236 histologic tests were collected. Three cases in category 1 indicated malignancy (1 melanoma). 201 of category 3 received a biopsy, where in 91 (45.3%) malignancy was confirmed. Teledermatology with digital images taken in primary care was feasible from a GP and from a specialist perspective. However, diagnostic appropriateness regarding avoidance of specialist care and possible missed skin cancer raises concerns. These results therefore question a promotion of teledermatology in clinical routine.


HEF1 promotes epithelial mesenchymal transition and bone invasion in prostate cancer under the regulation of microRNA-145.
The principal problem arising from prostate cancer (PCa) is its propensity to metastasize to bones, and it's crucial to understand the mechanism of tumor progression to metastasis in order to develop therapies that may reduce the morbidity and mortality of PCa patients. Although we had identified that microRNA(miR)-145 could repress bone metastasis of PCa via regulating epithelial-mesenchymal transition (EMT) in previous study, it is still unknown how miR-145 regulated EMT. In the present study, we constructed a luciferase reporter system and identified HEF1 as a direct target of miR-145. More importantly, HEF1 was shown to promote migration, invasion and EMT of PC-3 cells, a human PCa cell line originated from a bone metastatic PCa specimen. And HEF1 was also shown to partially mediate miR-145 suppression of EMT and invasion. Furthermore, inhibition of HEF1 repressed bone invasion of PC-3 cells in vivo. Expression of HEF1 was negatively correlated with miR-145 in primary PCa and bone metastatic specimens, but HEF1 was higher in samples which were more likely to commit to bone metastasis or those with higher free prostate-specific antigen (fPSA) levels and Gleason scores. Taken together, these findings indicate that HEF1 promotes EMT and bone invasion in prostate cancer by directly targeted by miR-145, and miR-145 suppresses EMT and invasion, at least in part, through repressing HEF1.


The effects of a smoking cessation programme on health-promoting lifestyles and smoking cessation in smokers who had undergone percutaneous coronary intervention.
Smoking is a major risk factor for not only the occurrence of myocardial ischaemia but also recurrences of vascular stenosis. This study aimed to evaluate health-promoting lifestyles and abstinence rate after a smoking cessation programme. Sixty-two smokers who had undergone percutaneous coronary intervention were randomly assigned to either the experimental or control group. The experimental group (n = 30) received 10 phone counselling sessions and 21 short message service messages for abstinence and coronary disease prevention, whereas the control group (n = 32) received only the standard education. After the intervention, 14 members of the experimental group had switched to a non-smoking status, confirmed biochemically; moreover, their physical activity and stress management scores increased significantly. However, self-efficacy of smoking cessation was not reflected in the cotinine levels. Thus, it is necessary not only to increase self-efficacy but also to determine the factors that affect the success of smoking cessation so that they can be included in the intervention. Our results suggest that phone counselling and short message service messaging might be important tools for the realization of smoking cessation and lifestyle changes among patients who have undergone percutaneous coronary intervention.


Hepatocyte retinoid X receptor alpha-dependent regulation of lipid homeostasis and inflammatory cytokine expression contributes to alcohol-induced liver injury.
Hepatocyte retinoid X receptor alpha (RXRalpha)-deficient mice are more sensitive to ethanol toxicity than wild-type mice. Because RXRalpha-mediated pathways are implicated in lipid homeostasis and the inflammatory response, we hypothesized that a compromise in lipid metabolism and associated production of proinflammatory mediators are responsible for the hepatotoxicity observed in ethanol-treated hepatocyte RXRalpha-deficient mice. Wild-type and hepatocyte RXRalpha-deficient mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. After ethanol treatment, serum ALT levels increased significantly (4-fold) in hepatocyte RXRalpha-deficient mice, but not in the wild-type mice. Hepatic liver fatty acid binding protein (L-FABP) mRNA and protein levels were reduced due to RXRalpha deficiency. Ethanol induced L-FABP mRNA and protein in wild-type mice and provided protection against nonesterified fatty acid toxicity; however, this effect was absent in the mutant mice. Accordingly, hepatic nonesterified fatty acid level was increased in ethanol-fed mutant mice. Ethanol increased nuclear factor (NF)-kappaB binding activity in hepatocyte RXRalpha-deficient mice, but not in wild-type mice. In agreement, hepatic mRNA levels of proinflammatory cytokines and chemokines were increased to a greater extent in the mutant than in wild-type mice. Furthermore, signal transducer and activator of transcription factor (STAT) 3 and associated Bcl-xL induction was observed in ethanol-fed wild-type mice but not in ethanol-fed hepatocyte RXRalpha-deficient mice. Taken together, after ethanol treatment, hepatocyte RXRalpha deficiency results in lack of L-FABP induction, increased hepatic free fatty acids, NF-kappaB activation, and proinflammatory cytokines production and a lack of STAT3 activation, which in part may contribute to alcohol-induced liver damage.


Effects of combined treatment with coffee cherry and whole-body hyperthermia on the growth of spontaneous mammary tumours in SHN mice.
Based on findings that free access in drinking water of the extract of coffee cherry (CC), the residue left after the removal of coffee beans, and whole-body hyperthermia (WBH) induced by far-infrared ray (FIR) can markedly inhibit the growth of spontaneous mammary tumours of SHN mice, the effects of the combined treatment with these agents were examined in this study. The significant inhibition of tumour growth by single treatment with either CC or WBH was not enhanced by their combination. Meanwhile, the body weight loss during WBH was significantly decreased by CC. Normal and preneoplastic growth of mammary glands and plasma component levels were affected little by either treatment. The findings confirmed the "normalization effects" of CC usually obtained with natural products and stress the need for prudence in the choice of any agent, natural or synthetic, to be applied simultaneously to increase the efficacy of WBH.


Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status.
A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer. This was a prospective case-control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years. Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08-2.42] and 1.42 (95% CI, 0.94-2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk. In this population-based, nested case-control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions. These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour.


[Comparative study on the treatment of acromioclavicular joint dislocation: coracoclavicular ligament reconstruction combined with hook plate fixation or suture-anchor fixation].
To investigate the clinical outcomes of acromioclavicula (AC) joint dislocation treated with coracoclavicular (CC) ligament reconstruction and hook plate fixation/suture-anchor fixation. There were 105 patients with Rockwood type III or severer AC joint dislocations were randomly divided into two groups from February 2007 to April 2010. They were treated with CC ligament reconstruction using double bundle of Palmaris longus (hook plate fixation group, 54 cases), and subsequently fixed with hook plates or suture-anchors (suture-anchors group, 51 cases). Patients were followed up, and the AC distance and CC distance were measured on the postoperative X-ray films, and the outcomes were assessed according to Karlsson criteria and Constant-Murley shoulder score. Ranked data was analyzed with the use of χ(2) test and measurement data with two sample t test. Eighty-nine patients were followed up for 24-42 months, average 30 months. There were 46 cases in hook plate fixation group and 43 cases in suture-anchor fixation group, without significant difference in age, gender, injured side and Rockwood classification between both groups. Between the two groups, no statistical difference was detected in the AC and CC distance measured within 6 months after operation (P > 0.05). The AC and CC distances of hook plate fixation group measured in 24 months postoperatively were larger than those in suture-anchor fixation group, respectively (F = 1.904 and 1.854, P < 0.05). In hook plate fixation group, the AC and CC distances measured in 24 months postoperatively were larger than those measured in 6 month postoperatively, respectively (F = 1.863 and 1.842, P < 0.05). According to Constant-Murley shoulder score, the average score was 88.5 for hook plate fixation group and 92.7 for suture-anchor fixation group (F = 0.475, P = 0.017). According to Karlsson criteria, the excellent and good rate of the functional recovery was 95.4% in suture-anchor fixation group, better than hook plate fixation group (χ(2) = 4.564, P = 0.033). The clinical outcomes of AC joint dislocation treated with CC ligament reconstruction and suture-anchor fixation are better than those treated with CC ligament reconstruction and hook plate fixation. The AC and CC distances increase after the removal of hook plate, which may be associated with poor functional recovery.


On down-regulation of the immune response to metastatic malignant melanoma.
Treatment of metastatic malignant melanoma with interferon alpha (IFNalpha) results in objective remission in approximately 15% of patients. In a previous investigation, we found that about 50% of the patients achieved at least minor or short-lived remissions. In some tumours extensive areas of regressive tumour change occurred. However, even in these areas remnants of tumour cells were generally found. The short duration of the immune response in some patients and the incomplete eradication of the tumour can be due either to selection of non-immunogenic tumour cells or to down-regulation of the immune reactivity to the tumour. In the present paper, the expression of the zeta chain of the T cell receptor in CD3+ lymphocytes and the expression of CD28 in CD3+, CD4+ and CD8+ lymphocytes was studied in resectable melanoma metastases from 20 treated (IFNalpha or IFNalpha in combination with cisplatinum and dacarbazine) and 16 untreated patients. A double-staining technique was used, and the occurrence and distribution of lymphocytes showing down-regulation of the zeta chain or CD28 were separately registered in different areas of the metastases: close to the tumour cells in areas of unaffected tumour growth, in areas with regressive tumour changes, in areas with marked fibrosis and in stromal areas with densely packed lymphocytes. CD3+ zeta lymphocytes were found in all metastases, but their number and distribution varied considerably. Down-regulation of the zeta chain was most often found in areas of regressive changes. In contrast, T lymphocytes infiltrating close to the tumour cells had a stronger expression of the zeta chain (P = 0.016). Down-regulation was also found in stromal areas of densely packed lymphocytes and in areas of fibrosis. The pattern of down-regulation of CD28 in various subsets of lymphocytes was similar to that of zeta chain. The same pattern of down-regulation of CD28 and the zeta chain was found in both untreated and treated patients, indicating that the down-regulation is not due to treatment but to the release of immunosuppressor factors from areas with high tumour cell density or extensive destruction of tumour cells. These results concur well with the view that IFNalpha treatment can result in immune-mediated tumour cell destruction early in the treatment period and that this immune response to the tumour can be followed by immunosuppression within a few weeks.


Pollinator nutrition and its role in merging the dual objectives of pollinator health and optimal crop production.
Bee and non-bee insect pollinators play an integral role in the quantity and quality of production for many food crops, yet there is growing evidence that nutritional challenges to pollinators in agricultural landscapes are an important factor in the reduction of pollinator populations worldwide. Schemes to enhance crop pollinator health have historically focused on floral resource plantings aimed at increasing pollinator abundance and diversity by providing more foraging opportunities for bees. These efforts have demonstrated that improvements in bee diversity and abundance are achievable; however, goals of increasing crop pollination outcomes via these interventions are not consistently met. To support pollinator health and crop pollination outcomes in tandem, habitat enhancements must be tailored to meet the life-history needs of specific crop pollinators, including non-bees. This will require greater understanding of the nutritional demands of these taxa together with the supply of floral and non-floral food resources and how these interact in cropping environments. Understanding the mechanisms underlying crop pollination and pollinator health in unison across a range of taxa is clearly a win-win for industry and conservation, yet achievement of these goals will require new knowledge and novel, targeted methods. This article is part of the theme issue 'Natural processes influencing pollinator health: from chemistry to landscapes'.


Optimal search strategies for identifying mental health content in MEDLINE: an analytic survey.
General practitioners, mental health practitioners, and researchers wishing to retrieve the best current research evidence in the content area of mental health may have a difficult time when searching large electronic databases such as MEDLINE. When MEDLINE is searched unaided, key articles are often missed while retrieving many articles that are irrelevant to the search. The objectives of this study were to develop optimal search strategies to detect articles with mental health content and to determine the effect of combining mental health content search strategies with methodologic search strategies calibrated to detect the best studies of treatment. An analytic survey was conducted, comparing hand searches of 29 journals with retrievals from MEDLINE for 3,395 candidate search terms and 11,317 combinations. The sensitivity, specificity, precision, and accuracy of the search strategies were calculated. 3,277 (26.8%) of the 12,233 articles classified in the 29 journals were considered to be of interest to the discipline area of mental health. Search term combinations reached peak sensitivities of 98.4% with specificity at 50.0%, whereas combinations of search terms to optimize specificity reached peak specificities of 97.1% with sensitivity at 51.7%. Combining content search strategies with methodologic search strategies for treatment led to improved precision: substantive decreases in the number of articles that needed to be sorted through in order to find target articles. Empirically derived search strategies can achieve high sensitivity and specificity for retrieving mental health content from MEDLINE. Combining content search strategies with methodologic search strategies led to more precise searches.


The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype.
Excessive trabeculation of the cardiac left ventricular wall is a complex phenotypic substrate associated with various physiological and pathological processes. There has been considerable conjecture as to whether hypertrabeculation contributes to disease and whether left ventricular non-compaction (LVNC) cardiomyopathy is a distinct pathology. Building on recent insights into the genetic basis of LVNC cardiomyopathy, in particular three meta-analysis studies exploring genotype-phenotype associations using different methodologies, this review examines how genetic research can advance our understanding of trabeculation. Three groups of genes implicated in LVNC are described-those associated with other cardiomyopathies, other cardiac/syndromic conditions and putatively with isolated LVNC cardiomyopathy-demonstrating how these findings can inform the underlying pathologies in LVNC patients and aid differential diagnosis and management in clinical practice despite the limited utility suggested for LVNC genetic testing in recent guidelines. The outstanding questions and future research priorities for exploring the genetics of hypertrabeculation are discussed.


Cell-to-cell communication in cancer: workshop report.
Recent advances in cancer biology and the development of new research tools have enabled interrogations of single cells and cell-cell interactions. Emerging technologies are capable of revealing data on the physical characteristics of cells, differences in the genome and proteome between cancerous and healthy cells, and variations in distinct cell subpopulations. Dynamic measurements enable studies that can reveal the evolution of cell characteristics. Cells can also be assembled in vitro or ex vivo into two- and three-dimensional cell environments, allowing for studies of cell-cell interactions and cell signaling. The Memorial Sloan Kettering Cancer Center, in collaboration with the Breast Cancer Research Foundation and the National Cancer Institute, co-organized a workshop as an opportunity for leading researchers in their respective fields to present and discuss scientific research highlights relevant to the utilization of techniques and technologies for studying cell-to-cell communications in cancer. Avenues of future development and the potential for clinical utility were primary features of these discussions. The scientific presentations and extensive ensuing discussions resulted in the identification of a number of research opportunities, which are summarized in this report.


Perspective of asylum-seeking caregivers on the quality of care provided by a Swiss paediatric hospital: a qualitative study.
This study investigated the perspective of asylum-seeking caregivers on the quality of healthcare delivered to their children in a qualitative in-depth interview study. The health of asylum-seeking children is of key interest for healthcare providers, yet knowledge of the perspective of asylum-seeking caregivers when accessing healthcare is limited. The study took place in a paediatric tertiary care hospital in Basel, Switzerland. Interviews were done with 13 asylum-seeking caregivers who had presented with their children at the paediatric tertiary care hospital. Nine female and four male caregivers from Tibet, Eritrea, Afghanistan, Syria, Iraq, Albania and Macedonia were included. A diverse sample was chosen regarding cultural and social background, years of residence in Switzerland and reasons for seeking care. A previously developed and pilot-tested interview guide was used for semistructured in-depth interviews between 36 and 92 min in duration. Data analysis and reporting was done according to Consolidated Criteria for Reporting Qualitative Research. The number of interviews was determined by saturation of data. The interviewees described a mismatch of personal competencies and external challenges. Communication barriers and unfamiliarity with new health concepts were reported as challenges. These were aggravated by isolation and concerns about their child's health. The following factors were reported to strongly contribute to satisfaction of healthcare delivery: a respectful and trusting caregiver-provider relationship, the presence of interpreters and immediate availability of treatment. A mismatch of personal competencies and external challenges importantly influences the caregiver-provider relationship. To overcome this mismatch establishment of confidence was identified as a key factor. This can be achieved by availability of interpreter services, sufficient consultation time and transcultural trainings for healthcare workers. Coordination between the family, the government's asylum system and the medical system is required to facilitate this process.


Utilization of plasmapheresis in the management of bismuth intoxication with acute renal failure.
A 34-year-old female patient who ingested 2400 mg bismuth subcitrate in a suicide attempt was brought to the emergency department. She had mild encephalopathy and acute renal failure on admission. One session of plasmapheresis was performed to remove bismuth, and needed three sessions of hemodialysis and was discharged on the 24th day of hospitalization with the recovery of the renal function.


Quantifying the robustness of primary analysis results: A case study on missing outcome data in pairwise and network meta-analysis.
Conducting sensitivity analyses is an integral part of the systematic review process to explore the robustness of results derived from the primary analysis. When the primary analysis results can be sensitive to assumptions concerning a model's parameters (e.g., missingness mechanism to be missing at random), sensitivity analyses become necessary. However, what can be concluded from sensitivity analyses is not always clear. For instance, in a pairwise meta-analysis (PMA) and network meta-analysis (NMA), conducting sensitivity analyses usually boils down to examining how 'similar' the estimated treatment effects are from different re-analyses to the primary analysis or placing undue emphasis on the statistical significance. To establish objective decision rules regarding the robustness of the primary analysis results, we propose an intuitive index, which uses the whole distribution of the estimated treatment effects under the primary and alternative re-analyses. This novel index is compared to an objective threshold to infer the presence or lack of robustness. In the case of missing outcome data, we additionally propose a graph that contrasts the primary analysis results to those of alternative scenarios about the missingness mechanism in the compared arms. When robustness is questioned according to the proposed index, the suggested graph can demystify the scenarios responsible for producing inconsistent results to the primary analysis. The proposed decision framework is immediately applicable to a broad set of sensitivity analyses in PMA and NMA. We illustrate our framework in the context of missing outcome data in both PMA and NMA using published systematic reviews.


Pharmacotherapy of post-transplant viral infections.
Management of a number of significant viral pathogens in transplant recipients remains challenging. To define an optimal antiviral approach to the management of cytomegalovirus (CMV), human herpes virus-6 (HHV-6), Epstein-Barr (EBV)-associated post-transplant lymphoproliferative disorder (PTLD), and polyoma virus-associated nephropathy in transplant recipients. Clinical trials and existing data regarding use of antiviral agents for these viruses were reviewed to develop evidence-based recommendations for their management. Weighing the current evidence regarding the use of valganciclovir as pre-emptive therapy or prophylaxis, the former approach offers a greater benefit for the overall prevention of CMV disease. Limited data show that prophylaxis with antiviral agents is associated with a reduction in the risk of EBV-associated PTLD. Treatment options for HHV-6 and polyoma virus-associated nephropathy are still limited.


How We Should Assess the Delivery of End-Of-Life Care in General Practice? A Systematic Review.
The majority of end-of-life (EOL) care occurs in general practice. However, we still have little knowledge about how this care is delivered or how it can be assessed and supported. (i) To review the existing evaluation tools used for assessment of the delivery of EOL care from the perspective of general practice; (ii) To describe how EOL care is provided in general practice; (iii) To identify major areas of concern in providing EOL care in this context. A systematic review. Systematic searches of major electronic databases (Medline, EMBASE, PsycINFO, and CINAHL) from inception to 2017 were used to identify evaluation tools focusing on organizational structures/systems and process of end-of-life care from a general practice perspective. A total of 43 studies representing nine evaluation tools were included. A relatively restricted focus and lack of validation were common limitations. Key general practitioner (GP) activities assessed by the evaluation tools were summarized and the main issues in current GP EOL care practice were identified. The review of evaluation tools revealed that GPs are highly involved in management of patients at the EOL, but there are a range of issues relating to the delivery of care. An EOL care registration system integrated with electronic health records could provide an optimal approach to address the concerns about recall bias and time demands in retrospective analyses. Such a system should ideally capture the core GP activities and any major issues in care provision on a case-by-case basis.


Surveillance cultures and duration of carriage of multidrug-resistant Acinetobacter baumannii.
Isolating carriers of multidrug-resistant (MDR) Acinetobacter baumannii is the main measure to prevent its spread. Identification of carriers accompanied by contact precautions is essential. We aimed to determine the appropriate surveillance sampling sites and the duration of carriage of MDR A. baumannii. We studied prospectively two groups of patients from whom MDR A. baumannii was previously isolated: (i) those with recent clinical isolation (<or=10 days) and (ii) those with remote clinical isolation (>or=6 months). Screening for carriage was conducted from six sites: nostrils, pharynx, skin, rectum, wounds, and endotracheal aspirates. Strains recovered concurrently from different sites were genotyped using pulsed-field gel electrophoresis. Twelve of 22 with recent clinical isolation of MDR A. baumannii had >or=1 positive screening culture, resulting in a sensitivity of 55% when six body sites were sampled. Sensitivities of single sites ranged from 13.5% to 29%. Among 30 patients with remote clinical isolation, screening cultures were positive in 5 (17%), with a mean duration of 17.5 months from the last clinical culture. Remote carriers had positive screening cultures from the skin and pharynx but not from nose, rectum, wounds, or endotracheal aspirates. Eleven strains from five patients were genotyped. In all but one case, isolates from different sites in a given patient were clonal. Current methodology is suboptimal to detect MDR A. baumannii carriage. The sensitivity of surveillance cultures is low, even when six different body sites are sampled. The proportion of individuals with previous MDR A. baumannii isolation who remain carriers for prolonged periods is substantial. These data should be considered when designing measures to limit the spread of MDR A. baumannii.