Patient journey experiences may contribute to improve healthcare for patients with rare endocrine diseases.
Patient journeys are instruments developed by EURORDIS, The Voice of Rare Disease Patients in Europe, to collect patients' experiences; they may identify gaps and areas deserving improvement, as well as elements positively considered by affected persons. As with other patient-reported experiences, they can complete the clinical evaluation and management of a specific disease, improving the often long diagnostic delay, therapy, patient education and access to knowledgeable multidisciplinary teams. This review discusses the utility of such patient-reported experience measures and summarises the experiences of patients with acromegaly, Addison's disease and congenital adrenal hyperplasia from different European countries. Despite rare endocrine diseases being varied and presenting differently, feelings of not having been taken seriously by health professionals, family and friends was a common patient complaint. Empathy and a positive patient-centred environment tend to improve clinical practice by creating a trustworthy and understanding atmosphere, where individual patient needs are considered. Offering access to adequate patient information on their disease, treatments and outcome helps to adapt to living with a chronic disease and what to expect in the future, contemplating the impact of a disease on patients' everyday life, not only clinical outcome but also social, financial, educational, family and leisure issues is desirable; this facilitates more realistic expectancies for patients and can even lead to a reduction in health costs. Patient empowerment with patient-centred approaches to these complex or chronic diseases should be contemplated more and more, not only for the benefit of those affected but also for the entire health system.


Role of RpoS in virulence of pathogens.
Understanding mechanisms of bacterial pathogenesis is critical for infectious disease control and treatment. Infection is a sophisticated process that requires the participation of global regulators to coordinate expression of not only genes coding for virulence factors but also those involved in other physiological processes, such as stress response and metabolic flux, to adapt to host environments. RpoS is a key response regulator to stress conditions in Escherichia coli and many other proteobacteria. In contrast to its conserved well-understood role in stress response, effects of RpoS on pathogenesis are highly variable and dependent on species. RpoS contributes to virulence through either enhancing survival against host defense systems or directly regulating expression of virulence factors in some pathogens, while RpoS is dispensable, or even inhibitory, to virulence in others. In this review, we focus on the distinct and niche-dependent role of RpoS in virulence by surveying recent findings in many pathogens.


Edge anisotropy and the geometric perspective on flow networks.
Spatial networks have recently attracted great interest in various fields of research. While the traditional network-theoretic viewpoint is commonly restricted to their topological characteristics (often disregarding the existing spatial constraints), this work takes a geometric perspective, which considers vertices and edges as objects in a metric space and quantifies the corresponding spatial distribution and alignment. For this purpose, we introduce the concept of edge anisotropy and define a class of measures characterizing the spatial directedness of connections. Specifically, we demonstrate that the local anisotropy of edges incident to a given vertex provides useful information about the local geometry of geophysical flows based on networks constructed from spatio-temporal data, which is complementary to topological characteristics of the same flow networks. Taken both structural and geometric viewpoints together can thus assist the identification of underlying flow structures from observations of scalar variables.


Clinical usefulness of the pendulum test using a NK table to measure the spasticity of patients with brain lesions.
. [Purpose] The purpose of the present study was to investigate the clinical usefulness (reliability and validity) of the pendulum test using a Noland-Kuckhoff (NK) table with an attached electrogoniometer to measure the spasticity of patients with brain lesions. [Subjects] The subjects were 31 patients with stroke or traumatic brain injury. [Methods] The intraclass correlation coefficient (ICC) was used to verify the test-retest reliability of spasticity measures obtained using the pendulum test. Pearson's product correlation coefficient was used to examine the validity of the pendulum test using the amplitude of the patellar tendon reflex (PTR) test, an objective and quantitative measure of spasticity. [Results] The test-retest reliability was high, reflecting a significant correlation between the test and the retest (ICCs = 0.95-0.97). A significant negative correlation was found between the amplitude of the PTR test and the four variables measured in the pendulum test (r = -0.77- -0.85). [Conclusion] The pendulum test using a NK table is an objective measure of spasticity and can be used in the clinical setting in place of more expensive and complicated equipment. Further studies are needed to investigate the therapeutic effect of this method on spasticity.


A shear assay study of single normal/breast cancer cell deformation and detachment from poly-di-methyl-siloxane (PDMS) surfaces.
This paper presents the results of a combined experimental and analytical/computational study of viscoelastic cell deformation and detachment from poly-di-methyl-siloxane (PDMS) surfaces. Fluid mechanics and fracture mechanics concepts are used to model the detachment of biological cells observed under shear assay conditions. The analytical and computational models are used to compute crack driving forces, which are then related to crack extension during the detachment of normal breast cells and breast cancer cells from PDMS surfaces that are relevant to biomedical implants. The interactions between cells and the extracellular matrix, or the extracellular matrix and the PDMS substrate, are then characterized using force microscopy measurements of the pull-off forces that are used to determine the adhesion energies. Finally, fluorescence microscopy staining of the cytosketelal structures (actin, micro-tubulin and cyto-keratin), transmembrane proteins (vimentin) and the ECM structures (Arginin Glycine Aspartate - RGD) is used to show that the detachment of cells during the shear assay experiments occurs via interfacial cracking between (between the ECM and the cell membranes) with a high incidence of crack bridging by transmembrane vinculin structures that undergo pull-out until they detach from the actin cytoskeletal structure. The implications of the results are discussed for the design of interfaces that are relevant to implantable biomedical devices and normal/cancer tissue.


Differential Contributions of mSWI/SNF Chromatin Remodeler Sub-Families to Myoblast Differentiation.
Mammalian SWI/SNF (mSWI/SNF) complexes are ATP-dependent chromatin remodeling enzymes that are critical for normal cellular functions. mSWI/SNF enzymes are classified into three sub-families based on the presence of specific subunit proteins. The sub-families are Brm- or Brg1-associated factor (BAF), ncBAF (non-canonical BAF), and polybromo-associated BAF (PBAF). The biological roles for the different enzyme sub-families are poorly described. We knocked down the expression of genes encoding unique subunit proteins for each sub-family, Baf250A, Brd9, and Baf180, which mark the BAF, ncBAF, and PBAF sub-families, respectively, and examined the requirement for each in myoblast differentiation. We found that Baf250A and the BAF complex were required to drive lineage-specific gene expression. KD of Brd9 delayed differentiation. However, while the Baf250A-dependent gene expression profile included myogenic genes, the Brd9-dependent gene expression profile did not, suggesting Brd9 and the ncBAF complex indirectly contributed to differentiation. Baf180 was dispensable for myoblast differentiation. The results distinguish between the roles of the mSWI/SNF enzyme sub-families during myoblast differentiation.


Determining nursing student knowledge, behavior and beliefs for breast cancer and breast self-examination receiving courses with two different approaches.
This study aimed to determine nursing student knowledge, behavior and beliefs for breast cancer and breast self-examination receiving courses with a traditional lecturing method (TLM) and the Six Thinking Hats method (STHM). The population of the study included a total of 69 second year nursing students, 34 of whom received courses with traditional lecturing and 35 of whom received training with the STHM, an active learning approach. The data of the study were collected pre-training and 15 days and 3 months post-training. The data collection tools were a questionnaire form questioning socio-demographic features, and breast cancer and breast self-examination (BSE) knowledge and the Champion's Health Belief Model Scale. The tests used in data analysis were chi-square, independent samples t-test and paired t-test. The mean knowledge score following traditional lecturing method increased from 9.32 ± 1.82 to 14.41 ± 1.94 (P<0.001) and it increased from 9.20 ± 2.33 to 14.73 ± 2.91 after training with the Six Thinking Hats Method (P<0.001). It was determined that there was a significant increase in pre and post-training perceptions of perceived confidence in both groups. There was a statistically significant difference between pre-training, and 15 days and 3 months post-training frequency of BSE in the students trained according to STHM (p<0.05). On the other hand, there was a statistically significant difference between pre-training and 3 months post-training frequency of BSE in the students trained according to TLM. In both training groups, the knowledge of breast cancer and BSE, and the perception of confidence increased similarly. In order to raise nursing student awareness in breast cancer, either of the traditional lecturing method or the Six Thinking Hats Method can be chosen according to the suitability of the teaching material and resources.


[Hypotonic regulation in marine cladocerans Evadne nordmanni and Podon leuckarti].
At a salinity of the environment of 23-25% (delta degrees being equal to -1.28 divided by-1.39), the depression of hemolymph in E. nordmanni is equal to -0.76 +/- -0.11 degree, in P. leuckarti - to -0.75+/- -0.06 degree. This high level of hypotony persists up to the formation of the head-shild, after which the depression of marsupium fluid becomes equal to that of the external medium. It is suggested that the head-shield is involved into osmoregulation. Similarity of the level of the osmotic pressure of the internal medium in marine cladocerans and marine teleosts which also originated from fresh-water ancestors is noted.


[Somatoform disorders - a revision of the epidemiology in primary health care].
The prevalence of somatization is dependent on the classification methods and measures used to define it and the context from which the collected data are gathered. The aim of this study was to compare the prevalence of somatization and Somatoform Disorders (SFD) in Primary Health Care. A systematic review of the studies of the prevalence of somatization and SFD in PC (Primary Care) was made, from July 1998 to June 2009. The key words of this investigation, in Pub Med, were; somatoform disorders; somatization; somatisation; medically unexplained symptoms; MUS; functional somatic symptoms, the link with each of these key words having been made to Primary Care. A grid was drawn up for the selection of each article. The criteria for the inclusion of the studies took into account aspects related to the methodology and the instruments used (use of interview) and the clear definition of medically unexplained symptoms, amongst others. Twelve studies with prevalence values in a PC setting and 1 study of metaanalysis were selected. The values found for the total prevalence of SFD were extremely disperse, taking into consideration the various studies, being between 12% and 57.9%. The same results were found in relation to somatization disorder (between 0.5% and 16.1%) with 10.1%, referred to one study, following the very restrictive criteria of ICD-10. Results were more homogeneous for somatization defined by more abridged criteria, the Somatic Symptom Index 4.6 (SSI4,6) presenting values around 20% in almost the majority of selected studies that estimate the prevalence following this criteria. In the great majority of the studies, SFD increased the relative risk of other mental disorders (depressive and anxiety disorders). Some studies concluded that there was a relative independence of somatization in relation to those disorders, certified by the existence of a specific and cumulative effect of somatization (in relation to depressive and anxiety disorders) on the level of disability and of functional limitations as well as the level of use of resources in PC. This last decade has enabled a group of new studies that allow us to understand the extent of somatization in PC, especially in Europe and North America, and to have a more clearly based idea of the needs at service level and investigation level, within the referred area.


Influence of shoeing on ground reaction forces and tendon strains in the forelimbs of ponies.
Strains in the superficial digital flexor tendon (SDFT), deep digital flexor tendon (DDFT), accessory ligament of the deep digital flexor muscle (inferior check ligament [ICL]) and the interosseus medius muscle (suspensory ligament [SL]) in the right forelimb of 5 ponies were measured using mercury-in-silastic strain gauges a few hours after implantation. Tendon strains were recorded at the walk with normal flat shoes, egg-bar shoes, a 7 degrees increased hoof angle accomplished by application of a heel-wedge and a 7 degrees decreased hoof angle using a toe-wedge, consecutively. Ground reaction forces were recorded with all 4 shoe types preoperatively and with flat shoes post operatively. The strain patterns of the SDFT, DDFT and SL showed a rapid increase at the beginning of the stance phase, followed by a plateau with a small incline or decline and a rapid decrease at the end of the stance phase. The SDFT had its maximal strain in the first half of the stance phase in all ponies. The DDFT and SL reached their maximal strain in the first half of the stance phase in 2 ponies and in the second half of the stance phase in the other 3 ponies. The ICL was strained maximally in the second half of the stance phase in all ponies. Averaged over all 5 ponies, the maximal strains in the SDFT, DDFT, ICL and SL with normal flat shoes were 2.4, 1.3, 5.4 and 3.7%, respectively. If an egg-bar was applied the mean peak strain in the DDFT was 0.13% lower and strain in the SL was 0.22% higher. With a heel-wedge, strain decreased in the DDFT and ICL (0.19% and 0.4%, respectively) and increased by 0.24% in the SL. A toe-wedge increased strain in the ICL by 0.8%. All changes mentioned were statistically significant (P < 0.1). The changes in tendon strain as a result of different types of shoeing correlated with changes in calculated torque's of the ground reaction force acting on the coffin joint.


Competition-based model of pheromone component ratio detection in the moth.
For some moth species, especially those closely interrelated and sympatric, recognizing a specific pheromone component concentration ratio is essential for males to successfully locate conspecific females. We propose and determine the properties of a minimalist competition-based feed-forward neuronal model capable of detecting a certain ratio of pheromone components independently of overall concentration. This model represents an elementary recognition unit for the ratio of binary mixtures which we propose is entirely contained in the macroglomerular complex (MGC) of the male moth. A set of such units, along with projection neurons (PNs), can provide the input to higher brain centres. We found that (1) accuracy is mainly achieved by maintaining a certain ratio of connection strengths between olfactory receptor neurons (ORN) and local neurons (LN), much less by properties of the interconnections between the competing LNs proper. An exception to this rule is that it is beneficial if connections between generalist LNs (i.e. excited by either pheromone component) and specialist LNs (i.e. excited by one component only) have the same strength as the reciprocal specialist to generalist connections. (2) successful ratio recognition is achieved using latency-to-first-spike in the LN populations which, in contrast to expectations with a population rate code, leads to a broadening of responses for higher overall concentrations consistent with experimental observations. (3) when longer durations of the competition between LNs were observed it did not lead to higher recognition accuracy.


Musculoskeletal disorders and visual strain in intensive data processing workers.
This study was conducted for a UK Trade Union in response to increasing numbers of health complaints among intensive computer workers in a data processing environment. To estimate prevalence of musculoskeletal pain/discomfort and visual strain symptoms among data processing workers and to explore associations with work factors. A self-report questionnaire was distributed to data processors (n = 175) and a control group (n = 129) in the same organization. Eighty-six per cent of data processors reported musculoskeletal pain/discomfort in the previous year, with the highest prevalence rate found for the neck (58%). The 12 month reported prevalence for visual strain symptoms was 47%, tired eyes (41%) was the most commonly reported symptom. In the last week, 56% reported pain/discomfort and 25% visual strain symptoms. Data processors reporting pain in the previous year were more likely to be dissatisfied with their jobs (P < 0.01), to report a lack of choice in deciding what they did at work (P < 0.02), to have insufficient time to complete work (P < 0.05) or to receive help from others when time was limited (P < 0.03). The prevalence of self-reported musculoskeletal pain/discomfort and visual strain symptoms was high among data processors. A systematic approach to risk reduction addressing organizational, psychosocial and physical work factors is required. This study has implications for reorganization of this and other intensive computer work, given the increasing requirement for intensive computing work in many industrial sectors. More research is needed to investigate interactions between job demands and support systems for these workers.


Direct medical cost of stroke in Singapore.
Globally, stroke is recognized as one of the main causes of long-term disability, accounting for approximately 5·7 million deaths each year. It is a debilitating and costly chronic condition that consumes about 2-4% of total healthcare expenditure. To estimate the direct medical cost associated with stroke in Singapore in 2012 and to determine associated predictors. The National Healthcare Group Chronic Disease Management System database was used to identify patients with stroke between the years 2006 and 2012. Estimated stroke-related costs included hospitalizations, accident and emergency room visits, outpatient physician visits, laboratory tests, and medications. A total of 700 patients were randomly selected for the analyses. The mean annual direct medical cost was found to be S$12 473·7, of which 93·6% were accounted for by inpatient services, 4·9% by outpatient services, and 1·5% by A&E services. Independent determinants of greater total costs were stroke types, such as ischemic stroke (P = 0·005), subarachnoid hemorrhage (P < 0·001) and intracerebral haemorrhage (P < 0·001), shorter poststroke period, more than one complications (P = 0·045), and a greater number of comorbidities (P = 0·001). There is a considerable economic burden associated with stroke in Singapore. The type of stroke, length of poststroke period, and stroke complications and comorbidities are found to be associated with the total costs. Efforts to reduce inpatient costs and to allocate health resources to focus on the primary prevention of stroke should become a priority.


The role of mitochondrial superoxide anion (O2(-)) on physiological aging in C57BL/6J mice.
Much attention has been focused on the mitochondrial superoxide anion (O2(-)), which is also a critical free radial produced by ionizing radiation. The specific role of the mitochondrial O2(-) on physiological aging in mammals is still unclear despite wide-spread evidence that oxidative stress is involved in aging and age-related diseases. The major endogenous source of O2(-) is generated as a byproduct of energy metabolism from mitochondria. In order to better understand how O2(-)relates to metazoan aging, we have comprehensively examined age-related changes in the levels of oxidative damage, mitochondrial O2(-) production, mitochondrial antioxidant enzyme activity and apoptosis induction in key organs of an inbred mouse strain (C57BL/6J). Oxidative damage accumulated and excess apoptosis occurred in the brain, oculus and kidney with aging, but comparatively little occurred in the heart and muscle. These rates are correlated with O2(-) levels. Mitochondrial O2(-) production levels increased with aging in the brain, oculus and kidney, and did not significantly increased in the heart and muscle. In contrast to O2(-) production, mitochondrial SOD activities increased in heart and muscle, and remained unchanged in the brain, oculus and kidney with aging. These results suggest that O2(-) production has high organ specificity, and oxidative damage by O2(-) from mitochondria mediated apoptosis can lead to organ atrophy and physiological dysfunction. In addition, O2(-) from mitochondria plays a core role in physiological aging.


EHR and other IT adoption among physicians: results of a large-scale statewide analysis.
Despite a national push toward the adoption of health information technologies, much is still unknown about the use of IT in physician's offices. We surveyed all primary care physicians and a 25 percent stratified random sample of other specialists (total n=14,921) in Florida to better understand current trends and factors related to the use of IT in the ambulatory setting. Data was analyzed using logistic regression modeling techniques to compute adjusted odds ratios. Covariates included practice size, medical training, practice type, age, race, and gender Routine office computer use (80 percent) was found to be very common for administrative functions. The use of quality enhancing technologies such as PDAs (37.5 percent), use of e-mail with patients (16.6 percent) and EHR (23.7 percent) was less common. Overall, large practice size, specialty practice, physician age and gender, and multi-specialty practice affiliation were significantly related to the use of many, but not all, of these IT applications in the ambulatory setting.


Do consumers of manufactured cigarettes respond differently to price changes compared with their Roll-Your-Own counterparts? Evidence from New Zealand.
Price-based mechanisms are an important tobacco cessation policy tool in New Zealand (NZ) and so measurement of smokers' reaction to price changes is crucial in determining efficacy of this approach. Although approximately two-thirds of NZ tobacco demand is for manufactured cigarettes (MC) and one-third is for Roll-Your-Own (RYO) tobacco, previous price elasticity estimates have ignored differences between RYO tobacco and MC consumers. We employ a seemingly unrelated regression econometric approach applied to quarterly data over the period 1991-2011 to estimate price elasticities of demand separately for MC and RYO tobacco. Estimate of price elasticity of demand for MC is -1.033, and -0.441 for RYO tobacco. RYO tobacco is an inferior good; a 1% increase in average weekly income is associated with a 0.8% reduction in demand. RYO tobacco is a substitute for MC; a 1% increase in the price of MC is associated with a 0.867% increase in demand for RYO tobacco. There is significantly different price responsiveness across the two tobacco product types. MC smokers react far more strongly to price increases compared with RYO tobacco smokers. These findings suggest that pricing mechanisms may be more effective for reducing MC demand than for RYO tobacco. However, substitution between products means that this pricing effect is muted by the uptake of RYO tobacco use. Cessation policy specific to RYO use should be designed to target this growing group.


Association of interleukin-6 -174 G>C promoter polymorphism with increased risk of type 2 diabetes mellitus patients with diabetic nephropathy in Turkey.
Diabetic nephropathy (DN) is a serious complication of diabetes mellitus. We aimed to evaluate the interleukin (IL)-6 gene polymorphisms in type 2 DN and control subjects. The patients selected from the Department of Endocrinology and Metabolism Diseases included 43 type 2 diabetes mellitus patients without DN and 43 type 2 diabetes mellitus patients with DN and 340 healthy normal controls. All subjects underwent venous blood drawing for complete hormonal assays, lipid profile, glucose, and insulin and Il-6 gene polymorphism genetic analysis. IL-6 -174 G>C genotype distribution was different between the control group and the type 2 diabetes mellitus patients (p=0.004). The higher frequency of the polymorphic G allele was also similar for the group with type 2 diabetes mellitus as for the control group. The frequency of the polymorphic G allele was 83.9% in diabetic patients with nephropathy versus 70.9% in those without nephropathy (p=0.039). We suggest that the -174 G>C polymorphism of the IL-6 gene is an independent risk factor for DN in Turkish type 2 diabetes mellitus patients.


Reuse of a dyehouse effluent after being treated with the combined catalytic wet peroxide oxidation process and the aerated constructed wetland.
A catalytic wet peroxide oxidation process was combined with the aerated constructed wetland in order to treat the raw dyehouse wastewater to in acceptable level for reuse as washing process water. More than 90% of BOD and CODs could be removed with the wet peroxide oxidation reactor and the remaining pollutants in the treated water were transformed into biodegradable ones which could have been successfully treated at the following aerated constructed wetland. The highest values of BOD5, CODMn, CODCr, SS and T-N in the treated water were 1.6, 1.8, 2.1, 0.5 and 12.8 mg/L, respectively. These values were low enough for the treated water to be reused at the washing process.


Mutant cells selected during persistent reovirus infection do not express mature cathepsin L and do not support reovirus disassembly.
Persistent reovirus infections of murine L929 cells select cellular mutations that inhibit viral disassembly within the endocytic pathway. Mutant cells support reovirus growth when infection is initiated with infectious subvirion particles (ISVPs), which are intermediates in reovirus disassembly formed following proteolysis of viral outer-capsid proteins. However, mutant cells do not support growth of virions, indicating that these cells have a defect in virion-to-ISVP processing. To better understand mechanisms by which viruses use the endocytic pathway to enter cells, we defined steps in reovirus replication blocked in mutant cells selected during persistent infection. Subcellular localization of reovirus after adsorption to parental and mutant cells was assessed using confocal microscopy and virions conjugated to a fluorescent probe. Parental and mutant cells did not differ in the capacity to internalize virions or distribute them to perinuclear compartments. Using pH-sensitive probes, the intravesicular pH was determined and found to be equivalent in parental and mutant cells. In both cell types, virions localized to acidified intracellular organelles. The capacity of parental and mutant cells to support proteolysis of reovirus virions was assessed by monitoring the appearance of disassembly intermediates following adsorption of radiolabeled viral particles. Within 2 h after adsorption to parental cells, proteolysis of viral outer-capsid proteins was observed, consistent with formation of ISVPs. However, in mutant cells, no proteolysis of viral proteins was detected up to 8 h postadsorption. Since treatment of cells with E64, an inhibitor of cysteine-containing proteases, blocks reovirus disassembly, we used immunoblot analysis to assess the expression of cathepsin L, a lysosomal cysteine protease. In contrast to parental cells, mutant cells did not express the mature, proteolytically active form of the enzyme. The defect in cathepsin L maturation was not associated with mutations in procathepsin L mRNA, was not complemented by procathepsin L overexpression, and did not affect the maturation of cathepsin B, another lysosomal cysteine protease. These findings indicate that persistent reovirus infections select cellular mutations that affect the maturation of cathepsin L and suggest that alterations in the expression of lysosomal proteases can modulate viral cytopathicity.


EphrinB1 modulates glutamatergic inputs into POMC-expressing progenitors and controls glucose homeostasis.
Proopiomelanocortin (POMC) neurons are major regulators of energy balance and glucose homeostasis. In addition to being regulated by hormones and nutrients, POMC neurons are controlled by glutamatergic input originating from multiple brain regions. However, the factors involved in the formation of glutamatergic inputs and how they contribute to bodily functions remain largely unknown. Here, we show that during the development of glutamatergic inputs, POMC neurons exhibit enriched expression of the Efnb1 (EphrinB1) and Efnb2 (EphrinB2) genes, which are known to control excitatory synapse formation. In vivo loss of Efnb1 in POMC-expressing progenitors decreases the amount of glutamatergic inputs, associated with a reduced number of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits and excitability of these cells. We found that mice lacking Efnb1 in POMC-expressing progenitors display impaired glucose tolerance due to blunted vagus nerve activity and decreased insulin secretion. However, despite reduced excitatory inputs, mice lacking Efnb2 in POMC-expressing progenitors showed no deregulation of insulin secretion and only mild alterations in feeding behavior and gluconeogenesis. Collectively, our data demonstrate the role of ephrins in controlling excitatory input amount into POMC-expressing progenitors and show an isotype-specific role of ephrins on the regulation of glucose homeostasis and feeding.


Discordant results of CK-MB and troponin I measurements: a review of 14 cases.
In the course of a clinical comparison involving 204 parallel total creatine kinase (CK), creatine kinase-MB isoenzyme (CK-MB), and cardiac troponin I (cTnI) measurements, 12 patients were identified in whom cTnI was elevated while total CK was normal, as well as 2 patients in whom CK-MB was elevated while cTnI was normal. CK-MB relative index was elevated in 6 of the twelve cTnI-positive patients with normal total CK; only 2 of these patients had a discharge diagnosis of acute myocardial infarction (AMI). All of the 12 patients in this group had medical conditions that are associated with greater risk for acute cardiac events. Both patients with normal cTnI but elevated total CK and CK-MB index had chronic renal insufficiency; one of these patients had a positive stress test and a diagnosis of AMI. The other cTnI-negative patient died 2 days after admission, and autopsy revealed evidence of ischemic changes, but not acute infarction. Significant differences were apparent between traditional CK-MB results and cTnI measurements. Using total CK elevation as a prerequisite for subsequent CK-MB measurement may limit the clinical sensitivity of this enzyme marker for detecting subacute ischemic damage to the myocardium. Elevated total CK and CK-MB isoenzyme without corresponding elevations in cTnI, on the other hand, may reflect changes in enzyme elimination kinetics due to renal failure, or cross-reactivity of the cTnI assay with non-cardiac antigens.


Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression.
It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells, particularly mesenchymally derived stromal cells such as fibroblasts. However, the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts, suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand, 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions, or from distant metastases, were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together, these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage, allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites.


Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.
Calcific aortic valve disease (CAVD) is the most common heart disease of the developed world. It has previously been established that metformin administration reduces arterial calcification via autophagy; however, whether metformin directly regulates CAVD has yet to be elucidated. In the present study we investigated whether metformin alleviates valvular calcification through the autophagy-mediated recycling of Runx2. Calcification was reduced in rat valve interstitial cells (RVICs) by metformin treatment (0.5-1.5 mM) (P < 0.01), with a marked decrease in Runx2 protein expression compared to control cells (P < 0.05). Additionally, upregulated expression of Atg3 and Atg7 (key proteins required for autophagosome formation), was observed following metformin treatment (1 mM). Blocking autophagic flux using Bafilomycin-A1 revealed colocalisation of Runx2 with LC3 puncta in metformin treated RVICs (P < 0.001). Comparable Runx2 accumulation was seen in LC3 positive autolysosomes present within cells that had been treated with both metformin and hydroxychloroquine in combination (P < 0.001). Mechanistic studies employing three-way co-immunoprecipitation with Runx2, p62 and LC3 suggested that Runx2 binds to LC3-II upon metformin treatment in VICs. Together these studies suggest that the utilisation of metformin may represent a novel strategy for the treatment of CAVD.


Legacy Chemical Pollutants in House Dust of Homes of Pregnant African Americans in Atlanta.
We developed and applied a method for measuring selected persistent organic pollutants (POPs) (i.e., polybrominated diphenyl ethers (PBDEs), organochlorine pesticides, and polychlorinated biphenyls (PCBs)) in dust collected from pregnant African Americans (AAs) in Atlanta using isotope dilution gas chromatography-tandem mass spectrometry. Limits of quantification were ranged from 0.10 to 2.50 ng/g dust. NIST standard reference material measurements demonstrated the robustness of our method. Our accuracies ranged from 82 to 108%, relative standard deviations ranged from 2 to 16%, and extraction recoveries ranged from 76 to 102%. We measured POPs in dust collected from 34 homes of pregnant AAs participating in the Atlanta AA birth cohort study who were enrolled from 2016 to 2019. Concentrations of POPs were detected in all samples with the frequencies of detection ranging from 8 to 100%. Concentrations of PBDE congeners 99 and 47, p,p'-DDT, and PCB153 were detected at some of the highest concentrations with geometric means of 1270, 730, 63.4 and 240 ng/g, respectively. The ratio of DDT/DDE was quite large (~2.7) indicating that p,p'-DDT remains intact in homes for long periods of time. These data demonstrate that care should be taken to remediate POPs in indoor dust, especially in vulnerable, disparate segments of the population.


Amplification of migratory inhibition factor production during the first 48 hours of exposure to antigen.
When lymphocyte-macrophage suspensions from sensitized animals are preincubated with specific antigen for 24 or more h, the following results are observed. (i) In a standard capillary macrophage migration test, there is complete inhibition of migration. (ii) When the preincubated cell suspension is mixed in varying proportions with a similar suspension from nonsensitized animals and a macrophage migration test is performed, there is no linear relationship between the degree of inhibition of migration and the proportion of sensitized lymphocytes initially present. Inhibition thus appears to be an "all-or-none" effect. (iii) In spite of the second observation, increasing periods of preincubation with antigen result in increasing inhibition. (iv) These results suggest the existence of a complex amplifying mechanism operating within the early period of exposure to antigen. (v) To test the possibility that cell proliferation contributes to this amplification, cells from sensitized guinea pigs were irradiated with a dose of 1,000 rads prior to preincubation with antigen. Despite this dose, which virtually abolishes cell division in other systems, no diminution whatever in the amplification of inhibition was observed. These results suggest the existence of an early phase of increased production of migratory inhibition factor that is not dependent on cell division but that may be related to "recruitment" of nonsensitized lymphocytes.


Positioning errors in panoramic images in general dentistry in Sörmland County, Sweden.
The purpose of this study was to evaluate the frequency and severity of positioning errors in panoramic radiography in general dentistry. A total of 1904 digital panoramic radiographs, taken by the Public Dental Service in the county of Sörmland, Sweden, were analysed retrospectively. The study population consisted of all patients who underwent a panoramic examination during the year 2011. One experienced oral radiologist evaluated all radiographs for 10 common errors. Of the 1904 radiographs examined, 79 per cent had errors. The number of errors varied between 1-4 errors per image. No errors were found in 404 images (21%). Fifty-five images (3%) had severe errors, which made it impossible to make correct diagnostics. The most common error was the tongue not being in contact with the hard palate during exposure. However, this did not greatly affect the diagnostic usefulness of the image due to the ability to enhance the image.The patient's head was tilted too far upwards in 23 per cent of the images and the patient's head was rotated during exposure in 15 per cent. The least common error was due to patient movement during exposure (1%). Panoramic radiographs taken in general dental clinics in a Swedish county show several errors. Proper positioning of the patient is necessary to achieve panoramic images with good image quality. Some of the errors could be adjusted with the digital technique used.This allowed assessment of the images, which reduces radiation dose by avoiding retakes.


Effectiveness of a Nurse-Led Tele-Homecare Program for Patients With Multiple Chronic Illnesses and a High Risk for Readmission: A Randomized Controlled Trial.
Multiple chronic illnesses, such as those associated with advanced age, are leading causes of poor health, disability, death, and high healthcare expenditures. Tele-homecare is a novel method for providing home care to patients with chronic illnesses. The purpose of this study was to evaluate the effectiveness of an integrated nurse-led tele-homecare program for patients with multiple chronic illnesses and a high risk for readmission. A randomized controlled trial. Two hundred patients from a regional hospital who were scheduled to receive home care after discharge were randomly assigned to the intervention group (n = 100) or the control group (n = 100). The patients in the intervention group participated in an integrated tele-homecare program. For outcome evaluation, primary outcomes included the number of emergency department (ED) visits as well as readmittance and mortality. Secondary outcomes included patients' medication adherence, activities of daily living, health status, and quality of life (QOL). Data were collected at three time points: pretest baseline (T0), 3 months after intervention (T3), and 6 months after intervention (T6). A generalized estimating equation model was used to compare changes and evaluate the effect of differences between the two groups over time. For primary outcome evaluation, we found that the tele-homecare program significantly reduced mortality and ED visits, whereas no significant effect on readmission was observed. For secondary outcome evaluation, patients' QOL indicated significant improvement. The nurse-led tele-homecare program involves daily 24-hr remote monitoring and surveillance. In this study, the system detected patients' physical changes early and provided timely and appropriate management, consequently reducing ED visits and mortality. Additionally, it improved patients' QOL. On the basis of our findings, nurses' independent roles and functions revealed that the effectiveness of this nurse-led tele-homecare program strengthened the care of patients with multiple chronic illnesses.


Reflexive limb selection and control of reach direction to moving targets in cats, monkeys, and humans.
When we reach for an object, we have to decide which arm to use and the direction in which to move. According to the established view, this is voluntarily controlled and programmed in advance in time-consuming and elaborate computations. Here, we systematically tested the motor strategy used by cats, monkeys, and humans when catching an object moving at high velocity to the left or right. In all species, targets moving to the right selectively initiated movement of the right forelimb and vice versa for targets moving to the left. Movements were from the start directed toward a prospective target position. In humans, the earliest onset of electromyographic activity from start of motion of the target ranged from 90 to 110 ms in different subjects. This indicates that the selection of the arm and specification of movement direction did not result from the subject's voluntary decision, but were determined in a reflex-like manner by the parameters of the target motion. As a whole the data suggest that control of goal-directed arm movement relies largely on an innate neuronal network that, when activated by the visual signal from the target, automatically guides the arm throughout the entire movement toward the target. In the view of the present data, parametric programming of reaching in advance seems to be superfluous.


[Colonic interposition between kidney and psoas muscle: anatomical variation studied with CT].
Interposition of the colon between kidney and psoas muscle may represent a benign anatomical variant that can be recognized on Computed Tomography (CT) images. In our series including 428 abdominal CT examinations, the position of the bowel in the pararenal space was studied with respect to the kidney and the psoas muscle. To determine the colon position in the pararenal space, three CT scans, at the upper pole, midkidney and lower pole, for each side, were selected. The colonic interposition between the kidney and the psoas muscle was then correlated with patient's age, sex and amount of perinephric fat. The ascending colon was interposed between the kidney and the psoas muscle in 6/428 cases (1.4%), appearing more frequently in adult men. Of these 6 cases, CT showed decreased perinephric fat in three cases, normal in one and increased in two. No case of descending colonic interposition between the kidney and the psoas muscle was demonstrated. CT is a valuable tool to depict this anatomical variation, preventing misdiagnoses and complications arising from interventional procedures.


Effect of Surface Modification on Nano-Structured LiNi(0.5)Mn(1.5)O4 Spinel Materials.
Fine-tuning of particle size and morphology has been shown to result in differential material performance in the area of secondary lithium-ion batteries. For instance, reduction of particle size to the nanoregime typically leads to better transport of electrochemically active species by increasing the amount of reaction sites as a result of higher electrode surface area. The spinel-phase oxide LiNi0.5Mn1.5O4 (LNMO), was prepared using a sol-gel based template synthesis to yield nanowire morphology without any additional binders or electronic conducting agents. Therefore, proper experimentation of the nanosize effect can be achieved in this study. The spinel phase LMNO is a high energy electrode material currently being explored for use in lithium-ion batteries, with a specific capacity of 146 mAh/g and high-voltage plateau at ∼4.7 V (vs Li/Li(+)). However, research has shown that extensive electrolyte decomposition and the formation of a surface passivation layer results when LMNO is implemented as a cathode in electrochemical cells. As a result of the high surface area associated with nanosized particles, manganese ion dissolution results in capacity fading over prolonged cycling. In order to prevent these detrimental effects without compromising electrochemical performance, various coating methods have been explored. In this work, TiO2 and Al2O3 thin films were deposited using atomic layer deposition (ALD) on the surface of LNMO particles. This resulted in effective surface protection by prevention of electrolyte side reactions and a sharp reduction in resistance at the electrode/electrolyte interface region.


Human alpha-n-acetylglucosaminidase. 2. Activity towards natural substrates and multiple recognition forms.
Purified urinary alpha-N-acetylglucosaminidase acts as an exoglycosidase. The enzyme removes from heparan sulfate exclusively alpha-glycosidically linked N-acetylglucosamine residues. The pH optimum of around 4.4 towards heparan sulfate and heparin is similar to that towards synthetic arylglycosides. Urinary alpha-N-acetylglucosaminidase can be separated by isoelectric focusing into multiple forms with pI values between 3.3 and 6.0. The multiple forms differ in their recognition and endocytosis by cultivated skin fibroblasts. Forms with pI values of 4.8 +/- 0.3 respond best to endcytosis. From these forms up to 0.8 X 10(6) molecules may be recognized and taken up in an hour by a single cell. Sodium periodate treatment reduces the alpha-N-acetylglucosaminidase recognition by fibroblasts and suggests that the recognition sites on the enzyme are associated with its carbohydrate moiety. Attempts to modify the recognition of alpha-N-acetylglucosaminidase by pretreatment with purified glycosidases failed.


Optically active 4- and 5-coordinate transition metal complexes of bifurcated dipeptide Schiff bases.
Symmetrical and unsymmetrical benzophenone Schiff bases of bifurcated dipeptides [e.g., Ar2C=N-CHR1- CONH-HNCO-CHR2-N=CAr2] have been synthesized using Boc methodology. These ligands may be regarded as chiral porphyrin mimics because of the alpha-carbons of the amino acids. The Schiff bases function as effective ligands for transition metals, particularly the late transition metals Ni(II), Cu(II), and Zn. Upon metal insertion, there is loss of the amide protons, resulting in N4 chelating ligands that retain the amino acid based chirality as well as newly generated metal-centered chirality, which for the Ni(II) complexes have been shown by X-ray analysis to be lambda (left-handed helix) if the amino acids are S. For Ni(II) and Cu(II), metal insertion results in highly colored complexes and is easily followed by UV-vis spectrophotometry. Several Ni(II) complexes were also characterized by 1H NMR. Co(II) and Mn(II) complexes were characterized by CW EPR. Two Cu(II) complexes, 7f.CuII and 7k.CuII, were characterized by EPR (ENDOR and ESEEM), which clearly showed the pentacoordinate nature of 7k.CuII.


The combination of electric current and copper promotes neuronal differentiation of adipose-derived stem cells.
Damage to the nervous system can be caused by several types of insults, and it always has a great effect on the life of an individual. Due to the limited availability of neural transplants, alternative approaches for neural regeneration must be developed. Stem cells have a great potential to support neuronal regeneration. Human adipose-derived stem cells (hADSCs) have gained increasing interest in the fields of regenerative medicine due to their multilineage potential and easy harvest compared to other stem cells. In this study, we present a growth factor-free method for the differentiation of hADSCs toward neuron-like cells. We investigated the effect of electric current and copper on neuronal differentiation. We analyzed the morphological changes, the mRNA and protein expression levels in the stimulated cells and showed that the combination of current and copper induces stem cell differentiation toward the neuronal lineage with elongation of the cells and the upregulation of neuron-specific genes and proteins. The induction of the neuronal differentiation of hADSCs by electric field and copper may offer a novel approach for stem cell differentiation and may be a useful tool for safe stem cell-based therapeutic applications.


A parametric method for assessing diversification-rate variation in phylogenetic trees.
Phylogenetic hypotheses are frequently used to examine variation in rates of diversification across the history of a group. Patterns of diversification-rate variation can be used to infer underlying ecological and evolutionary processes responsible for patterns of cladogenesis. Most existing methods examine rate variation through time. Methods for examining differences in diversification among groups are more limited. Here, we present a new method, parametric rate comparison (PRC), that explicitly compares diversification rates among lineages in a tree using a variety of standard statistical distributions. PRC can identify subclades of the tree where diversification rates are at variance with the remainder of the tree. A randomization test can be used to evaluate how often such variance would appear by chance alone. The method also allows for comparison of diversification rate among a priori defined groups. Further, the application of the PRC method is not restricted to monophyletic groups. We examined the performance of PRC using simulated data, which showed that PRC has acceptable false-positive rates and statistical power to detect rate variation. We apply the PRC method to the well-studied radiation of North American Plethodon salamanders, and support the inference that the large-bodied Plethodon glutinosus clade has a higher historical rate of diversification compared to other Plethodon salamanders.


A pilot study of a traditional Chinese version of the University of Pennsylvania Smell Identification Test for application in Taiwan.
The 40-item University of Pennsylvania Smell Identification Test (UPSIT) is the most widely used smell test in the world. Presently, culturally modified versions of this test are available in 12 languages. This study describes the first assessment of a prototype traditional Chinese version of the UPSIT (UPSIT-TC) for administration in Taiwan. The goals were to determine the efficacy of specific items for testing Taiwanese subjects and to establish normative adjustments to allow for the use of North American norms. The American version of the UPSIT and the UPSIT-TC were administered to 40 healthy Taiwanese subjects on two test occasions separated from one another by 2 weeks. One subject was excluded because of invalid data. The mean UPSIT score was 28.3 (median, 28; SD, 3.8) for the first test administration and 28.5 (median, 28.0; SD, 4.4) for the second test administration. The mean UPSIT-TC score was 33.1 (median, 33.0; SD, 2.9) for the first administration and 32.8 (median, 33.0; SD, 3.6) for the second test administration. The UPSIT-TC scores were significantly higher than those of the UPSIT on both test occasions (p < 0.0001). Pearson correlations computed across the two test occasions were positive and statistically significant for both the UPSIT and the UPSIT-TC (respectively, r = 0.803 and 0.664; p < 0.0001). In accord with the modifications, the scores on the prototype UPSIT-TC were significantly higher than those on the American UPSIT when administered to a Taiwanese sample. Both versions of the UPSIT were stable across repeated test sessions.


Association of Nutrition Education and Its Interaction with Lifestyle Factors on Kidney Function Parameters and Cardiovascular Risk Factors among Chronic Kidney Disease Patients in Taiwan.
We evaluated the interactive effects of nutrition education (NE) and lifestyle factors on kidney function parameters and cardiovascular risk factors among chronic kidney disease (CKD) patients. This cross-sectional cohort study recruited 2176 CKD stages 3-5 patients aged > 20 years from Integrated Chronic Kidney Disease Care Network, Shuang Ho Hospital, Taiwan between December 2008 and April 2019. The multivariable regression analysis was performed to investigate the interactive effects of NE with lifestyle factors on kidney function parameters and cardiovascular risk factors. Relative excess risk due to interaction (RERI) and attributable proportion (AP) were applied to assess additive interaction. Patients who were smoking or physically inactive but received NE had better estimated glomerular filtration rate (eGFR) (β: 3.83, 95% CI: 1.17-6.49 or β: 3.67, 95% CI: 2.04-5.29) compared to those without NE. Patients with smoking and NE significantly reduced risks for having high glycated hemoglobin A1c (HbA1c) by 47%, high low-density lipoprotein cholesterol (LDL-C) by 38%, and high corrected calcium (C-Ca) by 50% compared to those without NE. Moreover, NE and smoking or inactive physical activity exhibited an excess risk of high C-Ca (RERI: 0.47, 95% CI: 0.09-0.85 for smoking or RERI: 0.46, 95% CI: 0.01-0.90 and AP: 0.51, 95% CI: 0.03-0.99 for physical activity). Our study suggests that CKD patients who were enrolled in the NE program had better kidney function. Thus, NE could be associated with slowing kidney function decline and improving cardiovascular risk factors.


Rapid in situ identification of biological specimens via DNA amplicon sequencing using miniaturized laboratory equipment.
In many parts of the world, human-mediated environmental change is depleting biodiversity faster than it can be characterized, while invasive species cause agricultural damage, threaten human health and disrupt native habitats. Consequently, the application of effective approaches for rapid surveillance and identification of biological specimens is increasingly important to inform conservation and biosurveillance efforts. Taxonomic assignments have been greatly advanced using sequence-based applications, such as DNA barcoding, a diagnostic technique that utilizes PCR and DNA sequence analysis of standardized genetic regions. However, in many biodiversity hotspots, endeavors are often hindered by a lack of laboratory infrastructure, funding for biodiversity research and restrictions on the transport of biological samples. A promising development is the advent of low-cost, miniaturized scientific equipment. Such tools can be assembled into functional laboratories to carry out genetic analyses in situ, at local institutions, field stations or classrooms. Here, we outline the steps required to perform amplicon sequencing applications, from DNA isolation to nanopore sequencing and downstream data analysis, all of which can be conducted outside of a conventional laboratory environment using miniaturized scientific equipment, without reliance on Internet connectivity. Depending on sample type, the protocol (from DNA extraction to full bioinformatic analyses) can be completed within 10 h, and with appropriate quality controls can be used for diagnostic identification of samples independent of core genomic facilities that are required for alternative methods.


Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms.
Trypanosoma brucei is the protozoan parasite that causes African trypanosomiasis, a neglected disease of people and animals. Co-metabolite analysis, labelling studies using [methyl-2H3]-methionine and substrate/product specificities of the cloned 24-SMT (sterol C24-methyltransferase) and 14-SDM (sterol C14demethylase) from T. brucei afforded an uncommon sterol metabolic network that proceeds from lanosterol and 31-norlanosterol to ETO [ergosta-5,7,25(27)-trien-3β-ol], 24-DTO [dimethyl ergosta-5,7,25(27)-trienol] and ergosterol [ergosta-5,7,22(23)-trienol]. To assess the possible carbon sources of ergosterol biosynthesis, specifically 13C-labelled specimens of lanosterol, acetate, leucine and glucose were administered to T. brucei and the 13C distributions found were in accord with the operation of the acetate-mevalonate pathway, with leucine as an alternative precursor, to ergostenols in either the insect or bloodstream form. In searching for metabolic signatures of procyclic cells, we observed that the 13C-labelling treatments induce fluctuations between the acetyl-CoA (mitochondrial) and sterol (cytosolic) synthetic pathways detected by the progressive increase in 13C-ergosterol production (control<[2-(13)C]leucine<[2-(13)C]acetate<[1-(13)C]glucose) and corresponding depletion of cholesta-5,7,24-trienol. We conclude that anabolic fluxes originating in mitochondrial metabolism constitute a flexible part of sterol synthesis that is further fluctuated in the cytosol, yielding distinct sterol profiles in relation to cell demands on growth.


dGTP triphosphohydrolase, a unique enzyme confined to members of the family Enterobacteriaceae.
The enzyme dGTP triphosphohydrolase (dGTPase; EC 126.96.36.199) was assayed in partially purified extracts of several genera of bacteria, and it was found to be strictly confined to members of the family Enterobacteriaceae. Whereas 11 of 12 enteric bacteria had comparable activity for this enzyme, 8 of 8 nonenteric bacteria, including species in the very closely related genera Vibrio and Aeromonas, did not assay positively for this enzyme. When challenged with Escherichia coli anti-dGTPase antiserum, the active enzymes fell into three groups, retaining 0, approximately 50, or 100% of their original activity. A computer search has revealed an amino acid sequence in the E. coli enzyme which matches well with the single-stranded-DNA binding motif of Prasad and Chiu (J. Mol. Biol. 193:579-584, 1987) and may account for the enzyme's observed interaction with DNA. As far as we are aware, this is the only enzymatic activity so far reported to be present solely in the enteric bacteria.


Correlation between international prostate symptom score and uroflowmetry in patients with benign prostatic hyperplasia.
To determine the correlation between severity of symptoms using the International Prostate Symptom Score (IPSS) and uroflowmetry in patients with lower urinary tract symptoms-benign prostatic hyperplasia (LUTS-BPH). We prospectively collected data from 51 consecutive men, who presented with LUTS-BPH at the Nnamdi Azikiwe University Teaching Hospital, Nnewi, Nigeria, from January 2012 through December, 2014. Symptom severity was assessed using the self-administered IPSS questionnaire. We also performed uroflowmetry using the Urodyn 1000 (Dantec, serial no. 5534). The mean age of the patients was 67.2 ± 9.7 years (range 40-89 years). The most common presenting IPSS-LUTS was nocturia (100%) followed by urinary frequency (98%), straining (92.0%), weak stream (84.3%), urgency (41.2%), incomplete voiding (39.2%), and intermittency (35.3%) Most of the patients had moderate symptoms (58.8%) on IPSS with a mean value of 13.5 ± 3.0. The mean Qmax was 15.6 ± 18.7 mL/s and the mean voided volume was 193.0 ± 79.2 mL. About one-third of the patients (39.2%) had an unobstructed flow pattern based on Qmax. Correlation analysis showed a weak correlation between IPSS and voiding time (r = 0.220, P > 0.05), flow time (r = 0.128, P > 0.05), and time to maximum flow (r = 0.246, P > 0.05). These correlations were not significant (P > 0.05). IPSS showed a negative correlation with maximum flow rate (r = 0.368; P < 0.0075), average flow rate (-0.203, P > 0.05), and voided volume (r = -0.164, P > 0.05). This negative correlation was significant for maximum flow rate. Correlation between IPSS and Qmax was negative but statistically significant. This implies that an inverse relationship exists between IPSS and Qmax, and remains the only important parameter in uroflowmetry. There was no statistically significant correlation between IPSS and the other variables of uroflowmetry.


Conjuring up creativity: the effect of performing magic tricks on divergent thinking.
Research suggests that learning to perform magic tricks can promote both physical and psychological wellbeing. The current study extended this work by examining the impact of learning magic tricks on divergent thinking. A group of 10- to 11-year-old children completed Guilford's Alternate Uses Test both before and after participating in either a magic-based, or art-based, activity. As predicted, compared to the art-based activity, the magic-based activity resulted in a significantly greater increase in both AUT Fluency and AUT Originality scores. Rosenberg's Self-Esteem Scale and Dweck's Implicit Theories of Intelligence Scale for Children was also completed after each activity, and participants' self-esteem scores were higher after the art-based activity than the magic-based activity. In an exploratory aspect of the study, the AUT was re-administered to both groups three weeks later, and yielded no significant differences. The practical and theoretical implications of these findings are discussed, along with recommendations for future research.


Generating a model of the three-dimensional spatial distribution of neurons using density maps.
Microcolumns are a vertical arrangement of neocortical neurons that may constitute a fundamental computational ensemble but have been difficult to study morphologically because of the challenges of determining the three-dimensional (3D) spatial arrangements of individual neurons in the ensemble. Previously, a statistical density map method was developed to characterize microcolumns using two-dimensional (2D) coordinates of neurons from thin tissue sections. Here we extend this approach to derive the relationship between these 2D density maps and the actual 3D properties of microcolumns by creating a theoretical 3D model of cortical neurons. In seven steps, we transform a 3D initial arrangement of neurons from a crystalline lattice, with distances and neuron numbers approximating the idealized cortical microcolumn as assayed by our 2D density map analysis, into a model whose neuronal locations represent a plausible 3D arrangement of neurons in the brain. Because we constrain the transformations on the 3D model by the 2D density map properties, the transformed 3D model will exhibit properties that are consistent with experimental findings regarding microcolumnar anatomy in the brain. Moreover, because our methodology only requires the x,y locations of neurons from thin sections, it is readily accessible to any set of input data regardless of preparation or staining, from human or animals. By generating 3D model neuronal arrangements and comparing between control, aged, and diseased brain, our method can be used to test hypotheses about the effects of neurological diseases as well as normal aging on the 3D structure of microcolumns in the brain.


Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude.
To investigate the possible mechanisms of adaptation to chronic hypoxia in the pulmonary circulation, we made direct measurements of pulmonary arterial pressure (Ppa) in 10 awake pika rodents that were transported to Xining, People's Republic of China (altitude 2,260 m) after being captured at 4,300 m and in 10 Wistar rats in a decompression chamber (simulated altitudes of 4,300 and 5,000 m) in Xining. Ppa was obtained at 1 h of exposure to each simulated altitude. The histology and immunohistochemistry of the lung tissues were also studied. Ppa in the pikas after the 4,300- and 5,000-m altitude exposures did not significantly increase, whereas in the rats Ppa rose significantly. Mean changes in Ppa from 2,260 to 4,300 and 5,000 m were 1.48 +/- 0.49 and 4.80 +/- 0.67 mmHg in the pikas and 10.38 +/- 3.36 and 19.10 +/- 2.28 mmHg in the rats. The ratio of right ventricular to left ventricular plus septal weight in the pikas and rats was 0.22 and 0.45, respectively. The pikas maintained levels of Hb, hematocrit, and 2,3-diphosphoglycerate lower than those of the rats. The percent wall thickness of the small pulmonary arteries in the pikas and rats was 9.22 and 27.21%, respectively, and it was well correlated with the degree of Ppa in both groups. Mast cells were observed in the lungs of the rats (7.1 +/- 0.33 cells/mm2) but not in the pikas. There was highly positive staining for mast cell tryptase and transforming growth factor-beta around pulmonary vessels in the rats, whereas no demonstrable reaction was observed in the pikas. We conclude that the pika has adapted to high altitude by losing hypoxic pulmonary vasoconstriction and thin-walled pulmonary arterioles.


Abstract 12670: Variability in Radiation Dose and Image Quality: A Comparison Across Fluoroscopy-system Vendors and Generations of Equipment.
Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances to reduce exposure during fluoroscopy. However there is currently little understanding of the dose-image quality (IQ) relationship between fluoroscopy vendors and across generations of equipment used for imaging during pediatric catheterization. We evaluated latest generation fluoroscopy systems from Phillips, Siemens, GE and Toshiba, and an older generation Phillips system (2004 release). Fluoroscopy and cineangiography were performed on a tissue simulation anthropomorphic phantom using a standardized imaging approach. Phantom surface exposures were used for Monte Carlo simulations to calculate radiation effective dose, accounting for differences in beam parameters. We also imaged a fluoroscopy IQ phantom to assess contrast-detail and line-per-inch visualization. IQ images were scored by 3 blinded reviewers with scores averaged to produce a composite rating (scale 0-18). To assess the impact of imaging approach we then simulated a neonatal cardiac catheterization incorporating "typical" imaging protocols provided by institutions using the various systems. Effective doses and IQ scores are summarized in the table. Effective doses varied by >400% with the older generation system consistently delivering markedly higher doses. The associated figure summarizes dose and IQ for a simulated neonatal cardiac catheterization which accounts for measured doses as well as the reported institutional imaging parameters summarized in the figure legend. These data demonstrate substantial technological improvements in fluoroscopy equipment and may be useful to justify institutional "upgrades". Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship that reflects both equipment and imaging approach.


What is the optimal cerebral perfusion pressure in children suffering from traumatic coma?
Head injury is a major cause of death and disability in children. Despite advances in resuscitation, emergency care, intensive care monitoring, and clinical practices, there are few data demonstrating the predictive value of certain physiological variables regarding outcome in this patient population. Mean arterial blood pressure (MABP), intracranial pressure (ICP), and cerebral perfusion pressure (CPP = MABP - ICP) are routinely monitored in patients in many neurological intensive care units throughout the world, but there is little evidence indicating that advances in care have been matched with corresponding improvements in outcome. Nonetheless, there is evidence that hypotension immediately following head injury is predictive of early death, and many patients with these features die with clinical signs of brain herniation caused by intracranial hypertension. Furthermore, available data indicate that a minimal and a mean CPP measured during intensive care are good predictors of outcome in survivors, but a target threshold to improve outcome has yet to be defined. Some medical management strategies can have detrimental effects, and there is now a good case for undertaking a controlled trial of immediate or delayed craniectomy. Independent outcome in children following severe head injury is associated with higher levels of CPP. The ability to tolerate different levels of CPP may be related to age, and therefore any such surgical trial would need a carefully defined protocol so that the potential benefit of such a treatment is maximized.


Bacterial Prostatitis: Bacterial Virulence, Clinical Outcomes, and New Directions.
Four prostatitis syndromes are recognized clinically: acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome, and asymptomatic prostatitis. Because Escherichia coli represents the most common cause of bacterial prostatitis, we investigated the importance of bacterial virulence factors and antimicrobial resistance in E. coli strains causing prostatitis and the potential association of these characteristics with clinical outcomes. A structured literature review revealed that we have limited understanding of the virulence-associated characteristics of E. coli causing acute prostatitis. Therefore, we completed a comprehensive microbiological and molecular investigation of a unique strain collection isolated from healthy young men. We also considered new data from an animal model system suggesting certain E. coli might prove important in the etiology of chronic prostatitis/chronic pelvic pain syndrome. Our human data suggest that E. coli needs multiple pathogenicity-associated traits to overcome anatomic and immune responses in healthy young men without urological risk factors. The phylogenetic background and accumulation of an exceptional repertoire of extraintestinal pathogenic virulence-associated genes indicate that these E. coli strains belong to a highly virulent subset of uropathogenic variants. In contrast, antibiotic resistance confers little added advantage to E. coli strains in these healthy outpatients. Our animal model data also suggest that certain pathogenic E. coli may be important in the etiology of chronic prostatitis/chronic pelvic pain syndrome through mechanisms that are dependent on the host genetic background and the virulence of the bacterial strain.


Gene expression in hepatocellular carcinoma: pilot study of potential transarterial chemoembolization response biomarkers.
To perform a feasibility study to explore the relationship between hepatocellular carcinoma genetics and transarterial chemoembolization treatment response to identify potential biomarkers associated with enhanced treatment efficacy. In this single-institution study, pretreatment hepatocellular carcinoma biopsy specimens for tumors in 19 patients (14 men, five women; mean age, 59 y) treated with chemoembolization between 2007 and 2013 were analyzed for a panel of 60 chemotherapy-sensitivity, hypoxia, mitosis, and inflammatory genes with the QuantiGene Plex 2.0 mRNA detection assay. Demographic, disease, and procedure data and tumor response outcomes were collected. Quantitative mRNA levels were compared based on radiologic response between tumors exhibiting complete response (CR) versus partial response (PR). The study sample included 19 biopsy specimens from tumors (mean size, 3.0 cm; grade 1, n = 6; grade 2, n = 9; grade 3, n = 4) in patients treated with a mean of two conventional chemoembolization sessions. Thirteen and six tumors exhibited CR and PR, respectively, at a mean of 116 days after treatment. Tumors with CR showed a significant increase in (P < .05) or trend toward (P < .1) greater (range, 1.49-3.50 fold) pretreatment chemotherapy-sensitivity and mitosis (ATF4, BAX, CCNE1, KIF11, NFX1, PPP3CA, SNX1, TOP2A, and TOP2B) gene mRNA expression compared with tumors with PR, in addition to lower CXCL10 levels (0.48-fold), and had significantly (P < .05) higher (1.65-fold) baseline VEGFA levels. Genetic signatures may allow prechemoembolization stratification of tumor response probability, and gene analysis may therefore offer an opportunity to personalize locoregional therapy by enhancing treatment modality allocation. Further corroboration of identified markers and exploration of their respective predictive capacity thresholds is necessary.


Amplification and novel locations of endogenous mouse mammary tumor virus genomes in mouse T-cell lymphomas.
Endogenous mouse mammary tumor virus genomes are amplified and located in novel cell DNA sequences in many mouse T-cell lymphomas. Transplanted tumors recovered from the same mouse strain and shown to be of independent origin by chromosomal analysis, by the presence of JH immunoglobulin gene rearrangements, or by the integration patterns of exogenous Moloney MuLV genomes frequently showed similar patterns of novel mouse mammary tumor virus-containing cell DNA fragments. This process of amplification and relocation can occur within a limited number of cell generations and in C57BL/6 mice does not lead to the synthesis of mature virus-encoded proteins. In some instances, amplified mouse mammary tumor virus genomes contained novel restriction cleavage sites in the gag-pol region. The restricted time course of occurrence, lack of synthesis of mature virion proteins, and apparent site specificity indicate that this process of retrovirus amplification differs significantly from virus replication after exogenous infection.


Delayed density-dependent prevalence of Sin Nombre virus antibody in Montana deer mice (Peromyscus maniculatus) and implications for human disease risk.
American hantaviruses cause a severe respiratory disease known as hantavirus pulmonary syndrome (HPS). In the United States, Sin Nombre virus (SNV), carried by the deer mouse ( Peromyscus maniculatus), is the etiologic agent in the majority of HPS cases. The relationship between deer mouse population density and SNV infection prevalence in deer mice is poorly understood. Our purpose was to clarify this relationship by demonstrating the existence of delayed-density-dependent prevalence of SNV infection in populations of wild deer mice. We also explored the relationship between SNV infection in deer mouse populations and the incidence of human HPS. The study population was 3,616 deer mice captured on 10 mark-recapture grids in Montana during May and September, 1994-2004. Using multivariate logistic regression analysis, we found a strong association between deer mouse population density in fall (September) and SNV antibody prevalence in deer mice the following spring (May). Other characteristics associated with SNV infection in deer mice in spring were: (1) presence of at least one infected deer mouse in the population the previous fall, (2) male gender, (3) adult age class, (4) presence of scars, (5) grassland and logged habitats, and (6) elevations below 1,300 m. There was a strong association between concurrently measured SNV antibody prevalence in deer mice and probable exposure of human HPS cases during the same time period. Human cases were more likely to occur during seasons when SNV antibody prevalence was at least 10% in deer mouse populations. These findings suggest that fall rodent population parameters could be used to help guide prevention efforts the following spring.


Correlates of motivation to prevent weight gain: a cross sectional survey.
BACKGROUND: This study is an application of the theory of planned behaviour (TPB) with additional variables to predict the motivations to prevent weight gain. In addition, variations in measures across individuals classified into Precaution Adoption Process stages (PAPM-stages) of behaviour change were investigated. METHODS: A cross-sectional survey among 979 non-obese Dutch adults aged 25-35 years was conducted. Multiple binary logistic regression analysis was conducted to assess the associations of Body Mass Index (BMI), demographic factors and psychosocial variables from the TPB with the intention to prevent weight gain. Differences in BMI, demographic and psychosocial factors between PAPM-stages were explored using one-way analysis of variance and chi-square tests. RESULTS: Eighty-five percent of respondents intended to prevent weight gain. Age, attitudes and risk perceptions related to weight gain were the strongest correlates of intention (age: OR = 1.12, 95%CI: 1.04-1.20; attitude OR = 7.91, 95%CI: 5.33-11.74; risk perception OR = 1.24, 95%CI: 1.11-1.38). Significant differences were detected between the PAPM-stages in almost all variables. Notably, perceived behavioural control was lowest among people who had decided to prevent weight gain. CONCLUSION: Messages to influence attitudes towards the prevention of weight gain and risk perception may affect people who are not yet motivated to prevent weight gain. Interventions increasing people's perceived behavioural control in overcoming barriers to prevent weight gain may help people to act on their intentions.


Malonyl-CoA: the regulator of fatty acid synthesis and oxidation.
In the catabolic state with no food intake, the liver generates ketones by breaking down fatty acids. During the nocturnal fast or longer starvation periods, this protects the brain, which cannot oxidize fatty acids. In 1977, we published a study in the JCI noting the surprising realization that malonyl-CoA, the substrate of fatty acid synthesis, was also an inhibitor of fatty acid oxidation. Subsequent experiments have borne out this finding and furthered our understanding of molecular metabolism.


Beta-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells.
MDA-MB-231 human breast cancer cells express high beta-adrenoceptor levels, predominantly the beta2 subtype. Receptor stimulation by isoproterenol evoked immediate reductions in DNA synthesis which were blocked completely by propranolol and were of the same magnitude as effects elicited by high concentrations of 8-Br-cAMP. Isoproterenol-induced inhibition of DNA synthesis was maintained throughout several days of exposure, resulting in a decrement in total cell number, and the effects were augmented by cotreatment with dexamethasone; an even greater effect was seen when cAMP breakdown was inhibited by theophylline, with or without addition of isoproterenol. Despite the persistent effect of isoproterenol, receptor downregulation was evident with as little as 1 h of treatment, and over 90% of the receptors were lost within 24 h. Receptor downregulation was paralleled by homologous desensitization of the adenylyl cyclase response to beta-adrenoceptor stimulation. Dexamethasone augmented the effects of isoproterenol on DNA synthesis but did not prevent receptor downregulation or desensitization. These results indicate that beta-adrenoceptors are effectively linked, through cAMP, to the termination of cell replication in MDA-MB-231 human breast cancer cells, and that activation of only a small number of receptors is sufficient for a maximal effect. Novel pharmacologic strategies that focus on cell surface receptors operating through adenylyl cyclase may offer opportunities to combat cancers that are unresponsive to hormonal agents, or that have developed multidrug resistance.


Purkinje cell loss is a characteristic of essential tremor.
This paper began as a letter to the editor, commenting on several methodological and conceptual problems with the paper by Rajput et al. [1]. We were asked by the editors to expand the paper to include a more general discussion of the role of the cerebellum in essential tremor (ET). The study of the neuropathological underpinnings of essential tremor (ET) is a relatively new undertaking. The purpose of this paper is three-fold. The first is to comment on methodological problems in a recently-published paper by Rajput et al., the major one being the small sample size of that study, which resulted in a Type II statistical error. Hence, one cannot conclude based on their data that there is no Purkinje cell (PC) loss in ET. Secondly, we comment on conceptual problems with that study, which suggested that PC loss might not be a featured characteristic of ET because it is also found in other disease states. We discuss why this is an erroneous conclusion. Our third purpose is to more broadly discuss the role of the cerebellum in ET, giving consideration to the wealth of clinical and postmortem data that have accumulated over recent years. In this discussion, we make the following points: (1) it is now generally recognized that ET is a disease of cerebellar systems dysfunction, (2) given the nature of the postmortem work, revealing the presence of several types of structural-anatomical changes within the cerebellum and absence of detectable changes in other brain regions, the most empirically-based explanation is that the primary problem in ET is in the cerebellum itself, (3) that the collection of cellular changes in the cerebellum in ET are also present in other cerebellar degenerations should add to rather than detract from the notion that ET is a disease of cerebellar degeneration.


Changes in the osmotic activity of liver and of kidney tissue caused by passage of sodium chloride, urea, and some other substances into cells.
The osmotic activity of liver tissue and of kidney cortex tested within 10 minutes after immersion in solutions of sodium chloride has been increased by procedures which introduce sodium chloride, urea or creatinin into the body in excess of its elimination. A substance formed by cell metabolism, namely urea, can increase the osmotic activity of liver and of kidney cells. The amino acids, glycine and arginine, under similar conditions have not increased the osmotic activity of liver or of kidney cortex.


Effects of the time-of-day (morning vs. afternoon) of implementing a combined physical and cognitive exercise program on cognitive functions and mood of older adults: A randomized controlled study.
This study examined the effects of the time of conducting a combined physical and cognitive exercise program on cognitive functions and the mood of older adults. We randomly assigned 17 participants (8 men, 9 women, age 73,24±3,75) to the morning group (AM Group), 18 (8 men, 10 women, age 73,11±4,84) to the afternoon group (PM Group), and they completed a 12-week, dual-task exercise program in the morning or the afternoon, respectively. Moreover, the waiting-list control group consisted of 12 participants (6 men, 6 women, age 73,25±5,93). The cognitive functions and the mood of the participants were assessed before and after the program by using the Neurobehavioral Cognitive Status Examination, and the short version of the Profile of Mood States, respectively. As a result, the exercise program conducted in the afternoon had broader effects on cognitive functions (increased Repetition and Memory) than in the morning (increased Repetition), or the waiting-list control group (increased Judgment). Moreover, the program in the afternoon tended to reduce Anger-Hostility, and Fatigue. In conclusion, conducting the exercise program in the afternoon might be more effective for improving cognitive functions and the mood of older adults than in the morning. However, there was heterogeneity between the groups despite the randomization. Therefore, we suggest conducting a more rigorously controlled study using a larger sample to validate these findings.


Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection.
NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient (Klrk1-/- ) Ly49H+ NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H- NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex.


Concurrent sulforaphane and eugenol induces differential effects on human cervical cancer cells.
The concept of combination of chemoprevention holds great potential for cancer management as lower, clinically tolerable doses of individual agents could be achieved through therapeutic synergy. However, elucidation of their possible interactions--additive, synergistic, or antagonistic--must be thoroughly studied before considering for clinical use. To evaluate the effect of combination treatment of sulforaphane (SFN) and eugenol on HeLa cells, the authors performed cell viability assay, apoptosis assay, and reverse transcription polymerase chain reaction for gene expression analysis. Calculations of combination effects were expressed as a combination index (CI) with CI < 1, CI = 1, or CI > 1 representing synergism, additivity, or antagonism, respectively. Simultaneous treatment with variable dose combinations of SFN and eugenol resulted in differential effects with an antagonistic effect at lower and synergistic at higher sub-lethal doses as reflected in cell cytotoxicity and apoptosis induction. Importantly, gemcitabine used in conjunction with the low- and high-dose combinations showed no significant cell death at lower doses suggesting that cell cytotoxicity is proportional to gemcitabine alone, whereas at higher sublethal doses of SFN and eugenol, it was found to act in a synergistic manner with gemcitabine. Furthermore, SFN and eugenol combinations at synergistic dose significantly downregulated the expression of Bcl-2, COX-2 and IL-β but not the antagonistic combinations. This study clearly indicates that 2 (or more) chemopreventive agents can act antagonistically or synergistically necessitating elucidation of possible mechanistic interactions for favorable and reliable outcomes of dietary components in the field of cancer prevention.


Asynchronous discussion: a comparison of larger and smaller discussion group size.
To explore the effect of size and strategy on asynchronous discussions (AD) in a small baccalaureate nursing program. As the prevalence of e-learning increases in nursing education, the use of AD as a learning strategy will increase. Because the AD can be engaging, group size should be considered to enhance learning. Descriptive, correlational, and quasi-experimental methodologies were used to gather and analyze data from 23 junior baccalaureate nursing students. Variables included differences in group size (12 versus 23) and strategy (Virtual Clinical Excursions versus faculty-developed questions). There was no statistically significant difference in student outcomes for group size or strategy. The data suggested that smaller group size would help students "dig deeper" into the content being explored. Student perception responses indicate that Virtual Clinical Excursions was more likely to prepare them for nursing and clinical practice. Future research should include larger sample sizes and more variety in the sample demographics.


Architecture and regulation of HtrA-family proteins involved in protein quality control and stress response.
Protein quality control is vital for all living cells and sophisticated molecular mechanisms have evolved to prevent the excessive accumulation of unfolded proteins. High-temperature requirement A (HtrA) proteases have been identified as important ATP-independent quality-control factors in most species. HtrA proteins harbor a serine-protease domain and at least one peptide-binding PDZ domain to ensure efficient removal of misfolded or damaged proteins. One distinctive property of HtrAs is their ability to assemble into complex oligomers. Whereas all examined HtrAs are capable of forming pyramidal 3-mers, higher-order complexes consisting of up to 24 molecules have been reported. Tight control of chaperone and protease function is of pivotal importance in preventing deleterious HtrA-protease activity. In recent years, structural biology provided detailed insights into the molecular basis of the regulatory mechanisms, which include unique intramolecular allosteric signaling cascades and the dynamic switching of oligomeric states of HtrA proteins. Based on these results, functional models for many family members have been developed. The HtrA protein family represents a remarkable example of how structural and functional diversity is attained from the assembly of simple molecular building blocks.


Identification of HKDC1 and BACE2 as genes influencing glycemic traits during pregnancy through genome-wide association studies.
Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.


Supracerebellar transtentorial approach to posterior temporomedial structures.
The supracerebellar transtentorial (SCTT) approach, a modification of the infratentorial supracerebellar approach, facilitates simple and minimally invasive access to posterior temporomedial structures without requiring retraction of the temporal or occipital lobe. The SCTT approach was used in 16 patients over a 3-year period. Eleven patients harbored tumors confined to, or located mainly within, the posterior hippocampal formation, three patients harbored aneurysms (one ruptured posterior cerebral artery [PCA] aneurysm at the P2-P3 junction, one ruptured giant PCA [P2] aneurysm, and one giant basilar artery-superior cerebellar artery aneurysm), one patient had juvenile-type moyamoya disease, and one patient suffered from medically intractable epilepsy. In these patients, the SCTT approach enabled tumor removal, aneurysm clipping, and vascular bypass procedures. The authors' experience suggests that this approach can be used routinely in treating lesions in the posterior temporomedial region.


A survey of scale insects in soil samples from Europe (Hemiptera, Coccomorpha).
In the last decades, several expeditions were organized in Europe by the researchers of the Hungarian Natural History Museum to collect snails, aquatic insects and soil animals (mites, springtails, nematodes, and earthworms). In this study, scale insect (Hemiptera: Coccomorpha) specimens extracted from Hungarian Natural History Museum soil samples (2970 samples in total), all of which were collected using soil and litter sampling devices, and extracted by Berlese funnel, were examined. From these samples, 43 scale insect species (Acanthococcidae 4, Coccidae 2, Micrococcidae 1, Ortheziidae 7, Pseudococcidae 21, Putoidae 1 and Rhizoecidae 7) were found in 16 European countries. In addition, a new species belonging to the family Pseudococcidae, Brevennia larvalis Kaydan, sp. n. and a new species of Ortheziidae, Ortheziola editae Szita & Konczné Benedicty, sp. n. are described and illustrated based on the adult female stage. Revised keys to the adult females of Brevennia and Ortheziola are presented.


Identification of bile acids in the serum and urine in cholestasis. Evidence for 6alpha-hydroxylation of bile acids in man.
In this qualitative study of the pattern of bile acid excretion in cholestasis, methods are described for the isolation of bile acids from large volumes of urine and plasma. The bile acids were subjected to a group separation and identified by combined gas chromatography-mass spectrometry. The techniques were developed to allow identification of the minor components of the bile acid mixture. Four bile acids that have not previously been described in human urine and plasma were detected, namely 3beta, 7alpha-dihydroxy-5beta-cholan-24-oic acid, 3alpha, 6alpha-dihydroxy-5beta-cholan-24-oic acid (hyodeoxycholic acid), 3alpha, 6alpha, 7alpha-trihydroxy-5beta-cholan-24-oic acid (hyocholic acid) and 3alpha, 7beta, 12alpha-trihydroxy-5beta-cholan-24-oic acid. In addition three C27 steroids were found; 26-hydroxycholesterol and a trihydroxy cholestane, probably 5 beta-cholestane-3alpha, 7alpha, 26-triol were found in the sulphate fraction of plasma and urine. In the plasma sample, a sulphate conjugate of 24-hydroxycholesterol was found. The presence of these compounds probably reflects the existence of further pathways for bile acid metabolism. It is not yet known whether this is a consequence of the cholestasis or whether they are also present in normal man, at much lower concentrations.


Contribution to the Discovery of a Novel Medicine for a Neuromuscular Disease and of other Promising Molecules for the Treatment of Neurodevelopmental and Neurodegenerative Diseases.
Nervous system disorders affect millions of people around the world, through a very broad range of diseases. Here we describe our contribution to find a treatment for patients suffering from three of those diseases. The first one, autism spectrum disorder (ASD), affects approximately one in every 59 children in US. The second one, spinal muscular atrophy (SMA) is a rare disease affecting 1 in 10000 live births worldwide, often leading to death if untreated. The third one, Alzheimer's disease (AD) is a very well known devastating disease with an estimated 50 million people living with AD and other dementia, a number expected to triple by 2050. Our strategy to address those diseases was directed towards the discovery of a selective vasopressin 1a (V1a) antagonist for ASD, a splicing modifier of the survival of motor neuron 2 (SMN2) for SMA, and finally a γ-secretase modulator (GSM) for AD. In the frame of our GSM project, we also reported the discovery of a bridge piperidine moiety as a bioisostere for a phenyl moiety with an improved drug-like profile.


[Diagnostic and therapeutic thoracoscopy in 83 cases of chronic pleurisy].
From May 1983 to June 1985 the authors performed a thoracoscopy as a diagnostic and therapeutic objective in 83 patients with chronic recurrent pleurisy; amongst these patients, 69 had know intra or extra thoracic cancer and the other 14 presented with an isolated pleurisy. Eight other patients had pleural carcinomatosis proven by needle biopsy and had pleural talc introduced by thoracoscopy. The examination was performed under local anaesthesia with neuroleptanalgesia; a rigid 7 mm diameter thoracoscope was used; the biopsies were performed uniquely on the parietal pleura using tropical forceps. The outcome was uncomplicated with no deaths nor any serious complications due to the method. The sensitivity of the pleural biopsy was 91.5% or 76 positive biopsies out of 83. 73 biopsies were metastatic and 3 were tuberculous pleurisies. The macroscopic appearance was strongly suggestive of malignancy in 78 patients and appeared inflammatory in 13, of whom 9 cases were positive on biopsy. The authors performed a pleural talcage in every case; a lasting pleural adhesion was obtained in 66 patients but regrettably there were 14 failures, the effusion recurring after removal of the drain. The authors stress the reduced number of incidents of pleural effusion, which confirms the good tolerance of pleural endoscopy.