Transport of an Mr approximately 300,000 Plasmodium falciparum protein (Pf EMP 2) from the intraerythrocytic asexual parasite to the cytoplasmic face of the host cell membrane.
The profound changes in the morphology, antigenicity, and functional properties of the host erythrocyte membrane induced by intraerythrocytic parasites of the human malaria Plasmodium falciparum are poorly understood at the molecular level. We have used mouse mAbs to identify a very large malarial protein (Mr approximately 300,000) that is exported from the parasite and deposited on the cytoplasmic face of the erythrocyte membrane. This protein is denoted P. falciparum erythrocyte membrane protein 2 (Pf EMP 2). The mAbs did not react with the surface of intact infected erythrocytes, nor was Pf EMP 2 accessible to exogenous proteases or lactoperoxidase-catalyzed radioiodination of intact cells. The mAbs also had no effect on in vitro cytoadherence of infected cells to the C32 amelanotic melanoma cell line. These properties distinguish Pf EMP 2 from Pf EMP 1, the cell surface malarial protein of similar size that is associated with the cytoadherent property of P. falciparum-infected erythrocytes. The mAbs did not react with Pf EMP 1. In one strain of parasite there was a significant difference in relative mobility of the 125I-surface-labeled Pf EMP 1 and the biosynthetically labeled Pf EMP 2, further distinguishing these proteins. By cryo-thin-section immunoelectron microscopy we identified organelles involved in the transit of Pf EMP through the erythrocyte cytoplasm to the internal face of the erythrocyte membrane where the protein is associated with electron-dense material under knobs. These results show that the intraerythrocytic malaria parasite has evolved a novel system for transporting malarial proteins beyond its own plasma membrane, through a vacuolar membrane and the host erythrocyte cytoplasm to the erythrocyte membrane, where they become membrane bound and presumably alter the properties of this membrane to the parasite's advantage.


The role of biotic forces in driving macroevolution: beyond the Red Queen.
A multitude of hypotheses claim that abiotic factors are the main drivers of macroevolutionary change. By contrast, Van Valen's Red Queen hypothesis is often put forward as the sole representative of the view that biotic forcing is the main evolutionary driver. This imbalance of hypotheses does not reflect our current knowledge: theoretical work demonstrates the plausibility of biotically driven long-term evolution, whereas empirical work suggests a central role for biotic forcing in macroevolution. We call for a more pluralistic view of how biotic forces may drive long-term evolution that is compatible with both phenotypic stasis in the fossil record and with non-constant extinction rates. Promising avenues of research include contrasting predictions from relevant theories within ecology and macroevolution, as well as embracing both abiotic and biotic proxies while modelling long-term evolutionary data. By fitting models describing hypotheses of biotically driven macroevolution to data, we could dissect their predictions and transcend beyond pattern description, possibly narrowing the divide between our current understanding of micro- and macroevolution.


Intergeneric phylogenetic relationships in catfishes of the Loricariinae (Siluriformes: Loricariidae), with the description of Fonchiiloricaria nanodon: a new genus and species from Peru.
Recent investigations in the upper Río Huallaga in Peru revealed the presence of an intriguing species of the Loricariinae. To characterize and place this species within the evolutionary tree of the subfamily, a molecular phylogeny of this group was inferred based on the 12S and 16S mitochondrial genes and the nuclear gene F-reticulon4. The phylogeny indicated that this distinctive species was a member of the subtribe Loricariina. Given its phylogenetic placement, and its unusual morphology, this species is described as a new genus and new species of Loricariinae: Fonchiiloricaria nanodon. This new taxon is diagnosed by usually possessing one to three premaxillary teeth that are greatly reduced; lips with globular papillae on the surface; the distal margin of lower lip bearing short, triangular filaments; the premaxilla greatly reduced; the abdomen completely covered by plates, with the plates between lateral abdominal plates small and rhombic; a caudal fin with 14 rays; the orbital notch absent; five lateral series of plates; dorsal-fin spinelet absent; preanal plate present, large and solid, and of irregular, polygonal shape, the caudal peduncle becoming more compressed posteriorly for the last seven to 10 plates.


Bone adaptation to altered loading after spinal cord injury: a study of bone and muscle strength.
Bone loss from the paralysed limbs after spinal cord injury (SCI) is well documented. Under physiological conditions, bones are adapted to forces which mainly emerge from muscle pull. After spinal cord injury (SCI), muscles can no longer contract voluntarily and are merely activated during spasms. Based on the Ashworth scale, previous research has suggested that these spasms may mitigate bone losses. We therefore wished to assess muscle forces after SCI with a more direct measure and compare it to measures of bone strength. We hypothesized that the bones in SCI patients would be in relation to the loss of muscle forces. Six male patients with SCI 6.4 (SD 4.3) years earlier and 6 age-matched, able-bodied control subjects were investigated. Bone scans from the right knee were obtained by pQCT. The knee extensor muscles were electrically stimulated via the femoral nerve, isometric knee extension torque was measured and patellar tendon force was estimated. Tendon force upon electrical stimulation in the SCI group was 75% lower than in the control subjects (p<0.01). Volumetric bone mineral density of the patella and of the proximal tibia epiphysis were 50% lower in the SCI group than in the control subjects (p<0.01). Cortical area was lower by 43% in the SCI patients at the proximal tibia metaphysis, and by 33% at the distal femur metaphysis. No group differences were found in volumetric cortical density. Close curvilinear relationships were found between stress and volumetric density for the tibia epiphysis (r(2)=0.90) and for the patella (r(2)=0.91). A weaker correlation with the tendon force was found for the cortical area of the proximal tibia metaphysis (r(2)=0.63), and none for the distal femur metaphysis. These data suggest that, under steady state conditions after SCI, epiphyseal bones are well adapted to the muscular forces. For the metaphysis of the long bones, such an adaptation appears to be less evident. The reason for this remains unclear.


A genome-wide survey of switchgrass genome structure and organization.
The perennial grass, switchgrass (Panicum virgatum L.), is a promising bioenergy crop and the target of whole genome sequencing. We constructed two bacterial artificial chromosome (BAC) libraries from the AP13 clone of switchgrass to gain insight into the genome structure and organization, initiate functional and comparative genomic studies, and assist with genome assembly. Together representing 16 haploid genome equivalents of switchgrass, each library comprises 101,376 clones with average insert sizes of 144 (HindIII-generated) and 110 kb (BstYI-generated). A total of 330,297 high quality BAC-end sequences (BES) were generated, accounting for 263.2 Mbp (16.4%) of the switchgrass genome. Analysis of the BES identified 279,099 known repetitive elements, >50,000 SSRs, and 2,528 novel repeat elements, named switchgrass repetitive elements (SREs). Comparative mapping of 47 full-length BAC sequences and 330K BES revealed high levels of synteny with the grass genomes sorghum, rice, maize, and Brachypodium. Our data indicate that the sorghum genome has retained larger microsyntenous regions with switchgrass besides high gene order conservation with rice. The resources generated in this effort will be useful for a broad range of applications.


Romo1 is a mitochondrial nonselective cation channel with viroporin-like characteristics.
Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels. Indeed, Romo1 forms a nonselective cation channel with its amphipathic helical transmembrane domain necessary for pore-forming activity. Notably, channel activity was specifically inhibited by Fe2+ ions, an essential transition metal ion in ROS metabolism. Using structural bioinformatics, we designed an experimental data-guided structural model of Romo1 with a rational hexameric structure. We propose that Romo1 establishes a new category of viroporin-like nonselective cation channel in eukaryotes.


A pedicled bone graft from the acromion: an anatomical investigation regarding surgical feasibility.
To investigate the technical feasibility of harvesting a vascularized bone graft from the acromion pedicled on the acromial branch. Complex fractures of the proximal humerus may result in partial or total avascular necrosis of the head fragment. Treatment of avascular necrosis of the humeral head is dependent upon the stage of disease as well as the dimension and location of necrosis. In general, the outcome is poor and complete restoration of the shoulder function is rarely attained. Contrary to osteonecrosis of carpal bones (where vascularized bone grafts have been routinely carried out for decades), reports of analogous procedures at the humeral head are anecdotal. Based on selective post-mortem computer-tomographic angiography of 5 and the dissection of 30 embalmed human cadaver shoulders, we describe the anatomy of the acromial branch of the thoracoacromial trunk. The main focus was the constancy of its anatomical course, its dimensions and potential use as a nutrient vessel for a pedicled bone graft from the acromion. The course of the acromial branch revealed a constant topographic relationship to anatomical landmarks. Its terminal branches reliably supplied the anterior part of the acromion. The vascularized bone graft could be sufficiently mobilized to allow tension-free transfer to the humeral head as well as to the lateral two-thirds of the clavicle. We demonstrated the feasibility of vascularized bone graft harvesting from the acromion. This technique could be a joint-preserving procedure for osteonecrosis of the humeral head or may assist in the revision of a clavicular pseudoarthrosis.


Neuronal activity and TrkB ligands influence Kv3.1b and Kv3.2 expression in developing cortical interneurons.
Among the GABAergic neocortical interneurons, fast-spiking (FS) basket and chandelier cells are essential mediators for feed-forward inhibition, network synchrony and oscillations. The FS properties are in part mediated by the voltage-gated potassium channels Kv3.1b/3.2 which allow the fast repolarization of the membrane necessary for firing non-adapting action potentials at high frequencies. It has been recently reported that the FS phenotype fails to mature in BDNF knockout mice suggesting a role for neurotrophins. We now describe the role of neuronal activity and neurotrophins for Kv3.1b/3.2 expression using organotypic cultures of rat visual cortex as model system. Chronic activity deprivation from 2 days in vitro (DIV) prevented the postnatal developmental increase of Kv3.2, but not Kv3.1b mRNA expression. However, chronic activity deprivation failed to alter Kv3.1b and marginally delayed Kv3.2 protein expression. Activity deprivation by glutamate receptor blockade from 10 to 20 DIV reduced both mRNAs, whereas deprivation with tetrodotoxin (TTX) reduced both mRNAs and the Kv3.2 protein. Thalamic and cortical afferents in cocultures failed to alter the expression. BDNF and NT4 supplemented from 2 DIV onwards increased the expression of Kv3.1b, but not Kv3.2 mRNA in young cultures. Only NT4 increased the expression of both mRNAs later in development. Kv3 protein levels were not changed by exogenous tropomyosin-related kinase B (TrkB) ligands, but the levels decreased upon inhibiting the MAPK signaling suggesting a role for endogenous factors and in particular MEK2 signaling for translation. The results show that Kv3.1b/3.2 expression is differentially controlled by neuronal activity and neurotrophic factors.


2011 German Escherichia coli O104:H4 outbreak: whole-genome phylogeny without alignment.
A large-scale Escherichia coli O104:H4 outbreak occurred in Germany from May to July 2011, causing numerous cases of hemolytic-uremic syndrome (HUS) and deaths. Genomes of ten outbreak isolates and a historical O104:H4 strain isolated in 2001 were sequenced using different new generation sequencing platforms. Phylogenetic analyses were performed using various approaches which either are not genome-wide or may be subject to errors due to poor sequence alignment. Also, detailed pathogenicity analyses on the 2001 strain were not available. We reconstructed the phylogeny of E. coli using the genome-wide and alignment-free feature frequency profile method and revealed the 2001 strain to be the closest relative to the 2011 outbreak strain among all available E. coli strains at present and confirmed findings from previous alignment-based phylogenetic studies that the HUS-causing O104:H4 strains are more closely related to typical enteroaggregative E. coli (EAEC) than to enterohemorrhagic E. coli. Detailed re-examination of pathogenicity-related virulence factors and secreted proteins showed that the 2001 strain possesses virulence factors shared between typical EAEC and the 2011 outbreak strain. Our study represents the first attempt to elucidate the whole-genome phylogeny of the 2011 German outbreak using an alignment-free method, and suggested a direct line of ancestry leading from a putative EAEC-like ancestor through the 2001 strain to the 2011 outbreak strain.


Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain's control circuit.
Based on brain imaging findings, we present a model according to which addiction emerges as an imbalance in the information processing and integration among various brain circuits and functions. The dysfunctions reflect (a) decreased sensitivity of reward circuits, (b) enhanced sensitivity of memory circuits to conditioned expectations to drugs and drug cues, stress reactivity, and (c) negative mood, and a weakened control circuit. Although initial experimentation with a drug of abuse is largely a voluntary behavior, continued drug use can eventually impair neuronal circuits in the brain that are involved in free will, turning drug use into an automatic compulsive behavior. The ability of addictive drugs to co-opt neurotransmitter signals between neurons (including dopamine, glutamate, and GABA) modifies the function of different neuronal circuits, which begin to falter at different stages of an addiction trajectory. Upon exposure to the drug, drug cues or stress this results in unrestrained hyperactivation of the motivation/drive circuit that results in the compulsive drug intake that characterizes addiction.


Major Effect of Oxidative Stress on the Male, but Not Female, SP-A1 Type II Cell miRNome.
Pulmonary surfactant protein A (SP-A) plays an important role in surfactant metabolism and lung innate immunity. In humans there are two proteins, SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2, respectively, which are produced by the alveolar type II cells (T2C). We sought to investigate the differential influence of SP-A1 and SP-A2 in T2C miRNome under oxidative stress (OxS). SP-A knock out (KO) and hTG male and female mice expressing SP-A1 or SP-A2 as well as gonadectomized (Gx) mice were exposed to O3-induced oxidative stress (OxS) or filtered air (FA). Expression of miRNAs and mRNAs was measured in the T2C of experimental animals. (a) In SP-A1 males after normalizing to KO males, significant changes were observed in the miRNome in terms of sex-OxS effects, with 24 miRNAs being differentially expressed under OxS. (b) The mRNA targets of the dysregulated miRNAs included Ago2, Ddx20, Plcg2, Irs1, Elf2, Jak2, Map2k4, Bcl2, Ccnd1, and Vhl. We validated the expression levels of these transcripts, and observed that the mRNA levels of all of these targets were unaffected in SP-A1 T2C but six of these were significantly upregulated in the KO (except Bcl2 that was downregulated). (c) Gondadectomy had a major effect on the expression of miRNAs and in three of the mRNA targets (Irs1, Bcl2, and Vhl). Ccnd1 was upregulated in KO regardless of Gx. (d) The targets of the significantly changed miRNAs are involved in several pathways including MAPK signaling pathway, cell cycle, anti-apoptosis, and other. In conclusion, in response to OxS, SP-A1 and male hormones appear to have a major effect in the T2C miRNome.


Evaluation of the delivery of survivorship care plans for South Asian female breast cancer survivors residing in Canada.
This paper focuses on phase iii of a study evaluating the development and implementation of a survivorship care plan (scp) that could ultimately improve post-treatment quality of life for South Asian (sa) breast cancer survivors (bcss). Evaluating the utility of the scp was important to understand how sociocultural influences might affect uptake of the scp by sa bcss, especially as they transition from treatment to community care. Post-treatment discharge planning using an individualized scp at discharge for sa female breast cancer patients with stage i or ii disease was offered as a pilot service to oncologists at BC Cancer's Fraser Valley and Abbotsford centres. A longitudinal study using a mixed-methods approach was used to evaluate the utility of that service at 1 year after discharge. Participants (n = 16) completed a survey about their scp delivery experience, and a 1-year post implementation survey about the scp content and its utility. Most participants reported the discharge appointments to be extremely or very helpful with respect to post-treatment care questions. All have visited their family physicians for follow-up as recommended. The three major sources of support were family, faith, and family physician. Qualitative responses from the health care professionals who developed or implemented the scps identified two challenges in scp delivery: engaging patients or family members in relationship, and translating key information through interpreters. It is important to evaluate the utility of scps for sa female survivors, who might differ from the general bcs population because of a different understanding of the disease; language barriers; strong influence of family members; societal stigmas; and personal, social, cultural, and religious beliefs and values. A formal nurse-led discharge appointment with discussions about follow-up care and an individualized scp outlining the short- and long-term effects of treatment are recommended. Particular attention has to be paid to the practical and psychosocial needs of sa bcss and their supporting family members.


The characterization of a new enzyme from rat liver mitochondria, oligophosphoglyceroyl-ATP 3'-phosphodiesterase.
By using an assay based on the precipitation of intact 14C-labelled substrate, an activity has been located in the mitochondrial fraction of rat liver which selectively hydrolyses the 3' ester link in the fairly recently discovered oligomeric tetraphosphate derivative of ATP and glyceric acid for which the structure 3-phospho[glyceroyl-gamma-triphospho-5'-adenosine-3'-3-phospho]n-glyceroyl- gamma-triphospho-5'-adenosine has been proposed [Hutchinson, Morris & Mowbray (1986) Biochem. J. 234, 623-627]. This enzyme activity (Mr 85,000) has been purified approx. 30-fold from washed mitochondria by (NH4)2SO4 precipitation and f.p.l.c. The apparent Km for substrate (adenosine equivalents) is around 35 microM. The recovery of total activity is about 20%, and this, allied to the relatively low Vmax. found in contrast with the rapid turnover of oligomer seen in post-ischaemic tissues, suggests that some activating factors have been lost in purification. Percoll-gradient studies confirm that the activity is mitochondrial and not lysosomal or endoplasmic-reticular. The activity is latent in intact mitochondria; it is not, however, associated with intact inner-membrane vesicles but released during their preparation, implying an intermembrane-space location. The product of the enzyme is proposed to be the monomeric unit 3-phosphoglyceroyl-gamma-triphospho-5'-adenosine, from which digestion with snake-venom phosphodiesterase releases ADP.


A genetic screen in Drosophila for metastatic behavior.
A genetic screen was designed in Drosophila to interrogate its genome for mutations sufficient to cause noninvasive tumors of the eye disc to invade neighboring or distant tissues. We found that cooperation between oncogenic RasV12 expression and inactivation of any one of a number of genes affecting cell polarity leads to metastatic behavior, including basement membrane degradation, loss of E-cadherin expression, migration, invasion, and secondary tumor formation. Inactivation of these cell polarity genes cannot drive metastatic behavior alone or in combination with other tumor-initiating alterations. These findings suggest that the oncogenic background of tissues makes a distinct contribution toward metastatic development.


Repeated freezing induces a trade-off between cryoprotection and egg production in the goldenrod gall fly, Eurosta solidaginis.
Internal ice formation leads to wholesale changes in ionic, osmotic and pH homeostasis, energy metabolism, and mechanical damage, across a small range of temperatures, and is thus an abiotic stressor that acts at a distinct, physiologically relevant, threshold. Insects that experience repeated freeze-thaw cycles over winter will cross this stressor threshold many times over their lifespan. Here, we examined the effect of repeatedly crossing the freezing threshold on short-term physiological parameters (metabolic reserves and cryoprotectant concentration) as well as long-term fitness-related performance (survival and egg production) in the freeze-tolerant goldenrod gall fly, Eurosta solidaginis We exposed overwintering prepupae to a series of low temperatures (-10, -15 or -20°C) with increasing numbers of freezing events (3, 6 or 10) with differing recovery periods between events (1, 5 or 10 days). Repeated freezing increased sorbitol concentration by about 50% relative to a single freezing episode, and prompted prepupae to modify long-chain triacylglycerols to acetylated triacylglycerols. Long-term, repeated freezing did not significantly reduce survival but did reduce egg production by 9.8% relative to a single freezing event. Exposure temperature did not affect any of these measures, suggesting that threshold crossing events may be more important to fitness than the intensity of stress in overwintering E. solidaginis.


A nuclear export signal is essential for the cytosolic localization of the Ran binding protein, RanBP1.
RanBP1 is a Ran/TC4 binding protein that can promote the interaction between Ran and beta-importin /beta-karyopherin, a component of the docking complex for nuclear protein cargo. This interaction occurs through a Ran binding domain (RBD). Here we show that RanBP1 is primarily cytoplasmic, but the isolated RBD accumulates in the nucleus. A region COOH-terminal to the RBD is responsible for this cytoplasmic localization. This domain acts heterologously, localizing a nuclear cyclin B1 mutant to the cytoplasm. The domain contains a nuclear export signal that is necessary but not sufficient for the nuclear export of a functional RBD In transiently transfected cells, epitope-tagged RanBP1 promotes dexamethasone-dependent nuclear accumulation of a glucocorticoid receptor-green fluorescent protein fusion, but the isolated RBD potently inhibits this accumulation. The cytosolic location of RanBP1 may therefore be important for nuclear protein import. RanBP1 may provide a key link between the nuclear import and export pathways.


Pit membrane structure is highly variable and accounts for a major resistance to water flow through tracheid pits in stems and roots of two boreal conifer species.
The flow of xylem sap in conifers is strongly dependent on the presence of a low resistance path through bordered pits, particularly through the pores present in the margo of the pit membrane. A computational fluid dynamics approach was taken, solving the Navier-Stokes equation for models based on the geometry of pits observed in tracheids from stems and roots of Picea mariana (black spruce) and Picea glauca (white spruce). Model solutions demonstrate a close, inverse relationship between the total resistance of bordered pits and the total area of margo pores. Flow through the margo was dominated by a small number of the widest pores. Particularly for pits where the margo component of flow resistance was low relative to that of the torus, pore location near the inner edge of the margo allowed for greater flow than that occurring through similar-sized pores near the outer edge of the margo. Results indicate a surprisingly large variation in pit structure and flow characteristics. Nonetheless, pits in roots have lower resistance to flow than those in stems because the pits were wider and consisted of a margo with a larger area in pores.


Mutants of phage bIL67 RuvC with enhanced Holliday junction binding selectivity and resolution symmetry.
Viral and bacterial Holliday junction resolvases differ in specificity with the former typically being more promiscuous, acting on a variety of branched DNA substrates, while the latter exclusively targets Holliday junctions. We have determined the crystal structure of a RuvC resolvase from bacteriophage bIL67 to help identify features responsible for DNA branch discrimination. Comparisons between phage and bacterial RuvC structures revealed significant differences in the number and position of positively-charged residues in the outer sides of the junction binding cleft. Substitutions were generated in phage RuvC residues implicated in branch recognition and six were found to confer defects in Holliday junction and replication fork cleavage in vivo. Two mutants, R121A and R124A that flank the DNA binding site were purified and exhibited reduced in vitro binding to fork and linear duplex substrates relative to the wild-type, while retaining the ability to bind X junctions. Crucially, these two variants cleaved Holliday junctions with enhanced specificity and symmetry, a feature more akin to cellular RuvC resolvases. Thus, additional positive charges in the phage RuvC binding site apparently stabilize productive interactions with branched structures other than the canonical Holliday junction, a feature advantageous for viral DNA processing but deleterious for their cellular counterparts.


Early and long term results of coronary artery bypass grafts in patients with dialysis dependent renal failure.
Coronary artery disease is the main cause of mortality and morbidity in patients on renal therapy replacement. The aim of this study was to define peri-operative risk and long term results of coronary artery bypass grafts (CABG) in dialysis patients. this retrospective study included 82 patients in chronic dialysis who underwent CABG between 1978 and 1997. The mean age was 61+/-10 years (range 28-81 years), 84% of the patients were male and the average duration of dialysis was 57 months (range 1-148 months). Combined procedures were carotid endarterectomy in one case, left ventricular aneurysm resection in one and valvular replacement in 10 (nine aortic and one mitral replacements). The operation was elective in 42 patients (51 %) and urgent in the others. Previous myocardial infarction was found in 37 patients (45%) and left ventricular ejection fraction (LVEF) at less than 45% in 15 patients (18%); 23 patients (28%) were in NYHA class III or IV and regarding angina functional status, 77% in CCS class 3 or 4. Follow-up was complete. Statistical analysis included 30 and pre and peri-operative data. Statistical analysis used Chi-square analysis or Fisher's exact test, and the Mann-Whitney test when appropriate. The estimated probability of survival, including postoperative mortality, was calculated by the method of Kaplan-Meyer, and the Log-Rank test used to compare the results. the hospital mortality was 14.6 % (n = 12). Ischemic time and ECC time were significantly lengthened in dead patients (P = 0.01). Moreover, use of internal mammary artery was directly related to lower hospital mortality (P = 0.02). For previous myocardial infarction, LVEF at less than 45%, diabetes and combined procedure, a P-value of < or = 0.1 was calculated. The follow-up ranged from 1 to 140 months (mean 36 months). There were 39 late deaths. The survival rates (included hospital mortality) were 71+/-5%, 56+/-6% and 39+/-6% at 1, 3 and 5 years, respectively. All surviving patients improved their functional status and had symptomatic relief. Statistical analysis showed significant difference in favor of long term survival for patients younger than 60 years, LVEF > 45% and NYHA class I or II. these data confirm that CABG in patients with renal replacement therapy is associated with an high operative and long term mortality. However it allows an improvement of functional status, and so, let possible duration of dialysis. It may be expected that more active prevention and detection of coronary disease might improve these results.


Supratentorial and Infratentorial Lesions in Spinocerebellar Ataxia Type 3.
Background: Spinocerebellar ataxia type 3 (SCA) is a cerebellum-dominant degenerative disorder that is characterized primarily by infratentorial damage, although less severe supratentorial involvement may contribute to the clinical manifestation. These impairments may result from the efferent loss of the cerebellar cortex and degeneration of the cerebral cortex. Method: We used the three-dimensional fractal dimension (3D-FD) method to quantify the morphological changes in the supratentorial regions and assessed atrophy in the relatively focal regions in patients with SCA3. A total of 48 patients with SCA3 and 50 sex- and age-matched healthy individuals, as the control group, participated in this study. The 3D-FD method was proposed to distinguish 97 automatic anatomical label regions of gray matter (left cerebrum: 45, right cerebrum: 45, cerebellum: 7) between healthy individuals and patients with SCA3. Results: Patients with SCA3 exhibited reduced brain complexity within both the traditional olivopontocerebellar atrophy (OPCA) pattern and specific supratentorial regions. The study results confirmed the extensive involvement of extracerebellar regions in SCA3. The atrophied regions of SCA3 in infratentorial and supratentorial cortex showed a wide range of overlapped areas as in two functional cortexes, namely cerebellum-related cortex and basal ganglia-related cortex. Conclusions: Our results found that the atrophy of the SCA3 are not only limited in the infratentorial regions. Both cerebellar related cortex and basal ganglia related cortex were affected in the disease process of SCA3. Our findings might correlate to the common symptoms of SCA3, such as ataxia, Parkinsonism, dysarthria, and dysmetria. SCA3 should no longer be considered a disease limited to the cerebellum and its connections; rather, it should be considered a pathology affecting the whole brain.


Genomics education for health educators in Texas: the Family Health History Training Program.
This paper describes the development and pilot-testing of The Family Health History Training Program for Health Educators (FHHTP). Although in recent years professional organizations have urged the health promotion workforce to adopt genomics-related competencies, training opportunities designed specifically for health educators (HEs) remain scarce. Designed by a team of HEs, the FHHTP aims at preparing HEs in the state of Texas, USA, to use a family health history as a genomic health promotion tool. In this report, we describe (a) the program's empirical and theoretical grounding, (b) its components, and (c) pilot-testing of the 2 main components (Web-based and workshop trainings). The FHHTP addresses the training needs expressed by HEs and anchors itself in a theoretical model previously tested with 1,607 US-based HEs. The model draws from Social Cognitive Theory, the Theory of Planned Behavior, and Diffusion of Innovations theory. The program comprises 6 elements; the Web-based training and the training workshops are the focus of this paper. Pilot data indicate participants' knowledge and intention improved significantly (p < 0.05) at post-test and remained significantly higher at the 3-month follow-up. Attitudes, self-efficacy, behavior, knowledge/awareness, and intention also exhibited improvement in scores over time. We conclude, therefore, that the FHHTP can contribute significantly to the adoption of genomic competencies by Texas HEs. This report describes how the first-of-its-kind genomics training for HEs in the USA - FHHTP - was developed and pilot-tested with HEs in Texas.


Palatability in sheep and in vitro nutritional value of dried and ensiled sainfoin (Onobrychis viciifolia) birdsfoot trefoil (Lotus corniculatus), and chicory (Cichorium intybus).
Three temperate forages, sainfoin, birdsfoot trefoil, and chicory, characterized by elevated contents of plant secondary compounds, were compared to a ryegrass-clover mixture (control) in dried (Experiment 1) and ensiled form (Experiment 2) in their palatability and nutritional value. Palatability was measured in adult wethers (n = 6) allowed to choose between the familiar control forage and one of the three test plants. Palatability index was calculated from differences in intake of control and test plants measured after given times. Generally at first contact, palatability of the unfamiliar plants was low. Lag time until palatability index approached or exceeded a value of 100 was 2-5 d, but could not be related to the content of condensed tannins. Sainfoin had a high palatability, the highest content of condensed tannins (77.4 +/- 10.23 g/kg DM), a high content of duodenally utilisable crude protein (94.7 +/- 16.87 g/100 g CP), and a high content of metabolizable energy (9.5 +/- 0.38 MJ ME/kg DM), making this plant most promising for various purposes including anthelmintic action.


Negative regulation of Armadillo, a Wingless effector in Drosophila.
Drosophila Armadillo and its vertebrate homolog beta-catenin play essential roles both in the transduction of Wingless/Wnt cell-cell signals and in the function of cell-cell adherens junctions. Wingless and Wnts direct numerous cell fate choices during development. We generated a mutant protein, Armadillo(S10), with a 54 amino acid deletion in its N-terminal domain. This mutant is constitutively active in Wingless signaling; its activity is independent of both Wingless signal and endogenous wild-type Armadillo. Armadillo's role in signal transduction is normally negatively regulated by Zeste-white 3 kinase, which modulates Armadillo protein stability. Armadillo(S10) is more stable than wild-type Armadillo, suggesting that it is less rapidly targeted for degradation. We show that Armadillo(S10) has escaped from negative regulation by Zeste white-3 kinase, and thus accumulates outside junctions even in the absence of Wingless signal. Finally, we present data implicating kinases in addition to Zeste white-3 in Armadillo phosphorylation. We discuss two models for the negative regulation of Armadillo in normal development and discuss how escape from this regulation contributes to tumorigenesis.


Direct evidence for opposite effects of D-glucose and D-glyceraldehyde on cytoplasmic pH of mouse pancreatic beta-cells.
The effects of D-glucose, D-glyceraldehyde, glibenclamide, D-600, NH4+ and high concentrations of K+ on cytoplasmic pH (pHi) were investigated in dispersed and cultured pancreatic beta-cells from ob/ob mice. The cytoplasmic pH was measured with the fluorescent H+-indicator quene 1. The average pHi value in resting beta-cells was 6.71. Addition of 20 mM of the physiological stimulus D-glucose increased pHi with 0.05 units. Both glibenclamide and high concentrations of K+ decreased pHi. The latter effects were completely reversed by D-600, supporting the notion that free cytoplasmic Ca2+ can be involved in the regulation of pHi. In contrast to D-glucose, 10 mM of D-glyceraldehyde decreased pHi by 0.09 units, an effect persisting even in the presence of D-600. From the present study it is evident that D-glyceraldehyde and D-glucose have opposite effects on pHi in pancreatic beta-cells.


Abnormal Cardiac Biomarkers in Patients with Systemic Lupus Erythematosus and No Prior Heart Disease: A Consequence of Antimalarials?
Cardiac involvement in systemic lupus erythematosus (SLE) is often undiagnosed in its early phases. Specific heart biomarkers may identify patients at risk. We sought to investigate the prevalence and associated factors for such biomarkers in SLE. Brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) were measured simultaneously in 151 consecutive patients with no history of heart disease or pulmonary arterial hypertension (PAH). None had electrocardiographic abnormalities suggestive of acute coronary syndrome. Cross-sectional comparisons and logistic regression analyses were performed. Patients with abnormal biomarkers were investigated to delineate the specific cause. Sixteen patients (16/151, 10.6%) had elevated BNP, and 9 of them also had abnormal cTnI. Compared to subjects with normal biomarkers, they were older, had longer disease and antimalarial (AM) use duration, and more frequently persistent creatine phosphokinase (CPK) elevation. Multivariable regression analysis showed prolonged AM treatment (> 5.6 yrs) and persistent CPK elevation to be important predictors for elevated cardiac biomarkers. Six patients were diagnosed with definite (based on endomyocardial biopsy, n = 2) or possible (based on cardiac magnetic resonance after exclusion of other causes) AM-induced cardiomyopathy (AMIC); all had both BNP and cTnI elevated. Alternative causes were identified in 5, while no definitive diagnosis could be made in the remaining patients. About 10% of patients with SLE had elevated myocardial biomarkers, in the absence of prior cardiac disease or PAH. One-third of them were diagnosed with AMIC. Prolonged AM therapy and persistent CPK elevation conferred an increased risk for abnormal BNP and cTnI, which might predict AMIC.


Radioactive iodine thyroid uptake in patients with amiodarone-iodine-induced thyroid dysfunction.
Amiodarone, an iodine-rich drug, represents at the present, at least in Europe, one of the most common sources of iodine-induced thyroid dysfunction. The drug may induce both hypothyroidism and thyrotoxicosis. In spite of the large iodine intake occurring during amiodarone therapy, 131I thyroid uptake is detectable in patients with amiodarone-iodine-induced hypothyroidism, irrespective of the presence or absence of underlying thyroid disease. In contrast, in patients with amiodarone-iodine-induced thyrotoxicosis, 131I thyroid uptake is normal or even elevated in those with co-existent underlying thyroid disorders, whereas it is very low in those with an apparently normal thyroid gland. Perchlorate discharge test was performed in 8 patients with hypothyroidism and in 5 patients with hyperthyroidism induced by amiodarone: a positive test was found in all hypothyroid patients and a negative test in all hyperthyroid patients.


Understanding the Barriers and Facilitators to Sharing Patient-Generated Health Data Using Digital Technology for People Living With Long-Term Health Conditions: A Narrative Review.
Using digital technology to share patient-generated health data has the potential to improve the self-management of multiple long-term health conditions. Sharing these data can allow patients to receive additional support from healthcare professionals and peer communities, as well as enhance their understanding of their own health. A deeper understanding of the concerns raised by those living with long-term health conditions when considering whether to share health data via digital technology may help to facilitate effective data sharing practices in the future. The aim of this review is to identify whether trust, identity, privacy and security concerns present barriers to the successful sharing of patient-generated data using digital technology by those living with long-term health conditions. We also address the impact of stigma on concerns surrounding sharing health data with others. Searches of CINAHL, PsychInfo and Web of Knowledge were conducted in December 2019 and again in October 2020 producing 2,581 results. An iterative review process resulted in a final dataset of 23 peer-reviewed articles. A thorough analysis of the selected articles found that issues surrounding trust, identity, privacy and security clearly present barriers to the sharing of patient-generated data across multiple sharing contexts. The presence of enacted stigma also acts as a barrier to sharing across multiple settings. We found that the majority of literature focuses on clinical settings with relatively little attention being given to sharing with third parties. Finally, we suggest the need for more solution-based research to overcome the discussed barriers to sharing.


Group sexual offending by juvenile females.
This study examined all group sexual offending cases in the Netherlands between 1995 and 2009 (n = 26) in which at least one juvenile female offender (n = 35) had been adjudicated. Information from court files showed that the majority of juvenile female group sexual offenders have (inter)personal problems and (sexual) abuse experiences. The aims of the offender groups in committing the offense could be categorized in three themes: harassing the victim, sexual gratification, and taking revenge. The reasons why juvenile female offenders participated in a group could be categorized into group dynamics versus instrumental reasons. The findings are contrasted with findings on juvenile male group sexual offenders. Implications of the findings for research and treatment are discussed.


The effect of N-methylation on the conformational landscape of alanine: the case of N-methyl-l-alanine.
The non-proteinogenic amino acid N-methyl-l-alanine has been brought into the gas phase using laser ablation techniques and studied by high resolution chirped pulse and molecular-beam Fourier transform microwave spectroscopies coupled to supersonic expansion. Four conformers showing the three types of hydrogen bond interactions I (NHO[double bond, length as m-dash]C), II (OHN) and III (N-HO-H) have been unambiguously identified, based on the comparison of the experimental rotational and 14N nuclear quadrupole constants with the calculated ab initio values. The observation of a type III conformer evidences the role of methyl groups in both sides to impose the steric hindrance, precluding the relaxation from type III to type I conformers and explains the responsibility for the unique conformational landscape observed in the case of NMA.


Phosphene Perception Relates to Visual Cortex Glutamate Levels and Covaries with Atypical Visuospatial Awareness.
Phosphenes are illusory visual percepts produced by the application of transcranial magnetic stimulation to occipital cortex. Phosphene thresholds, the minimum stimulation intensity required to reliably produce phosphenes, are widely used as an index of cortical excitability. However, the neural basis of phosphene thresholds and their relationship to individual differences in visual cognition are poorly understood. Here, we investigated the neurochemical basis of phosphene perception by measuring basal GABA and glutamate levels in primary visual cortex using magnetic resonance spectroscopy. We further examined whether phosphene thresholds would relate to the visuospatial phenomenology of grapheme-color synesthesia, a condition characterized by atypical binding and involuntary color photisms. Phosphene thresholds negatively correlated with glutamate concentrations in visual cortex, with lower thresholds associated with elevated glutamate. This relationship was robust, present in both controls and synesthetes, and exhibited neurochemical, topographic, and threshold specificity. Projector synesthetes, who experience color photisms as spatially colocalized with inducing graphemes, displayed lower phosphene thresholds than associator synesthetes, who experience photisms as internal images, with both exhibiting lower thresholds than controls. These results suggest that phosphene perception is driven by interindividual variation in glutamatergic activity in primary visual cortex and relates to cortical processes underlying individual differences in visuospatial awareness.


Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha,25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines.
Although prostatic cancer is often viewed as an androgen-dependent malignancy, a number of other hormones including 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] are now recognized to modulate its growth and differentiated phenotype. Seven different continuous human prostatic carcinoma cell lines were examined for the presence of biologically active receptors for 1alpha,25(OH)2D3. All seven lines were found to contain mRNA for the vitamin D receptor using an RNase protection assay. Six of the seven cell lines were found to have high-affinity saturable binding sites for 1alpha,25(OH)2D3. The seventh line was found to contain vitamin D receptors by sucrose gradient analysis. All seven lines were found to express 24-hydroxylase activity by a HPLC assay that measures the conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3. 24-Hydroxylase activity was up-regulated in all seven cell lines by preincubation with 1alpha,25(OH)2D3. In the presence of fetal bovine serum, the growth of four of the seven cell lines was inhibited. In the majority of cell lines growth inhibition was related not only to the number of receptors per cell, but also in inverse proportion to the 24-hydroxylase activity of each cell line. The ubiquitous presence of vitamin D receptor and 24-hydroxylase activity in human prostatic carcinoma cells suggests new alternatives for the pharmacological treatment of advanced prostatic cancer and implies that chemoprevention strategies could also make use of this endocrine axis.


Hidden biofilms in a far northern lake and implications for the changing Arctic.
Shallow lakes are common across the Arctic landscape and their ecosystem productivity is often dominated by benthic, cyanobacterial biofilms. Many of these water bodies freeze to the bottom and are biologically inactive during winter, but full freeze-up is becoming less common with Arctic warming. Here we analyzed the microbiome structure of newly discovered biofilms at the deepest site of a perennially ice-covered High Arctic lake as a model of polar microbial communities that remain unfrozen throughout the year. Biofilms were also sampled from the lake's shallow moat region that melts out and refreezes to the bottom annually. Using high throughput small subunit ribosomal RNA sequencing, we found more taxonomic richness in Bacteria, Archaea and microbial eukaryotes in the perennially unfrozen biofilms compared to moat communities. The deep communities contained both aerobic and anaerobic taxa including denitrifiers, sulfate reducers, and methanogenic Archaea. The water overlying the deep biofilms was well oxygenated in mid-summer but almost devoid of oxygen in spring, indicating anoxia during winter. Seasonally alternating oxic-anoxic regimes may become increasingly widespread in polar biofilms as fewer lakes and ponds freeze to the bottom, favoring prolonged anaerobic metabolism and greenhouse gas production during winter darkness.


Telomerase activity coevolves with body mass not lifespan.
In multicellular organisms, telomerase is required to maintain telomere length in the germline but is dispensable in the soma. Mice, for example, express telomerase in somatic and germline tissues, while humans express telomerase almost exclusively in the germline. As a result, when telomeres of human somatic cells reach a critical length the cells enter irreversible growth arrest called replicative senescence. Replicative senescence is believed to be an anticancer mechanism that limits cell proliferation. The difference between mice and humans led to the hypothesis that repression of telomerase in somatic cells has evolved as a tumor-suppressor adaptation in large, long-lived organisms. We tested whether regulation of telomerase activity coevolves with lifespan and body mass using comparative analysis of 15 rodent species with highly diverse lifespans and body masses. Here we show that telomerase activity does not coevolve with lifespan but instead coevolves with body mass: larger rodents repress telomerase activity in somatic cells. These results suggest that large body mass presents a greater risk of cancer than long lifespan, and large animals evolve repression of telomerase activity to mitigate that risk.


Eating like there's no tomorrow: Public awareness of the environmental impact of food and reluctance to eat less meat as part of a sustainable diet.
Reducing meat consumption is central to many of the scientific debates on healthy, sustainable diets because of the high environmental impact of meat production. Missing from these debates are the public perspectives about eating less meat and consideration of cultural and social values associated with meat. The aim of this study was to explore public awareness of the environmental impact of food and their willingness to reduce meat consumption. Twelve focus groups and four individual interviews were conducted with adults from a range of socio-economic groups living in both rural and urban settings in Scotland. Public understanding of the link between food, environment and climate change was explored, with a focus on meat and attitudes towards reducing meat consumption. Data were transcribed and analysed thematically. Three dominant themes emerged: a lack of awareness of the association between meat consumption and climate change, perceptions of personal meat consumption playing a minimal role in the global context of climate change, and resistance to the idea of reducing personal meat consumption. People associated eating meat with pleasure, and described social, personal and cultural values around eating meat. Some people felt they did not need to eat less meat because they had already reduced their consumption or that they only ate small quantities. Scepticism of scientific evidence linking meat and climate change was common. Changing non-food related behaviours was viewed as more acceptable and a greater priority for climate change mitigation. The study highlights the role meat plays in the diet for many people, beyond nutritional needs. If healthy, sustainable dietary habits are to be achieved, cultural, social and personal values around eating meat must be integrated into the development of future dietary recommendations.


"Internal and External Combined" Nonradiative Decay-Based Nanoagents for Photoacoustic Image-Guided Highly Efficient Photothermal Therapy.
Rational manipulation of nonradiative decay channels is of crucial significance to improve photothermal conversion efficiency (PCE) and design photothermal agents. We first used the "internal and external combined" nonradiative decay strategy to enhance PCE. Specifically, organic IR-Y6 NPs with strong NIR absorption and high molar extinction coefficient were prepared and characterized. By means of TD-DFT calculations and fs-TA spectroscopy, the dual nonradiative decay channels composed of the free rotor (external strategy) and ultrafast dark excited states (DESs) between S0 and S1 states (internal strategy) were proved, which significantly enhanced PCE, up to 66%. IR-Y6 NPs were applied to a mice tumor model for photoacoustic image-guided photothermal therapy, showing complete tumor ablation ability and good biocompatibility for the normal organs. This work is of significance to deeply understand the nonradiation decay mechanism and rational design of high-performance PTT agents.


Clinical Trial Simulations Based on Genetic Stratification and the Natural History of a Functional Outcome Measure in Creutzfeldt-Jakob Disease.
A major challenge for drug development in neurodegenerative diseases is that adequately powered efficacy studies with meaningful end points typically require several hundred participants and long durations. Prion diseases represent the archetype of brain diseases caused by protein misfolding, the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. There is no well-established trial method in prion disease. To establish a more powerful and meaningful clinical trial method in sCJD. A stratified medicine and simulation approach based on a prospective interval-cohort study conducted from October 2008 to June 2014. This study involved 598 participants with probable or definite sCJD followed up over 470 patient-years at a specialist national referral service in the United Kingdom with domiciliary, care home, and hospital patient visits. We fitted linear mixed models to the outcome measurements, and simulated clinical trials involving 10 to 120 patients (no dropouts) with early to moderately advanced prion disease using model parameters to compare the power of various designs. A total of 2681 assessments were done using a functionally orientated composite end point (Medical Research Council Scale) and associated with clinical investigations (brain magnetic resonance imaging, electroencephalography, and cerebrospinal fluid analysis) and molecular data (prion protein [PrP] gene sequencing, PrPSc type). Of the 598 participants, 273 were men. The PrP gene sequence was significantly associated with decline relative to any other demographic or investigation factors. Patients with sCJD and polymorphic codon 129 genotypes MM, VV, and MV lost 10% of their function in 5.3 (95% CI, 4.2-6.9), 13.2 (95% CI, 10.9-16.6), and 27.8 (95% CI, 21.9-37.8) days, respectively (P < .001). Simulations indicate that an adequately powered (80%; 2-sided α = .05) open-label randomized trial using 50% reduction in Medical Research Council Scale decline as the primary outcome could be conducted with only 120 participants assessed every 10 days and only 90 participants assessed daily, providing considerably more power than using survival as the primary outcome. Restricting to VV or MV codon 129 genotypes increased power even further. Alternatively, single-arm intervention studies (half the total sample size) could provide similar power in comparison to the natural history cohort. Functional end points in neurodegeneration need not require long and very large clinical studies to be adequately powered for efficacy. Patients with sCJD may be an efficient and cost-effective group for testing disease-modifying therapeutics. Stratified medicine and natural history cohort approaches may transform the feasibility of clinical trials in orphan diseases.


Regulation of progesterone receptor gene expression and growth in the rat uterus: modulation of estrogen actions by progesterone and sex steroid hormone antagonists.
Although the rat uterus has often been used as a model to study estrogen action, relatively little is known of the mechanism(s) by which estrogen regulates uterine progesterone receptor (PR) levels in this species. In the present study, we used immature ovariectomized rats to examine the regulation of PR gene expression and growth in the uterus by estradiol (E2) as well as hormonal modulators of E2 action, namely progesterone (P), the antiestrogen LY117018 (LY), and the antiprogestin RU486. Northern blot analyses revealed eight PR mRNA species ranging in size from 3.3-14 kilobases, with the most abundant being 7.1 kilobases. E2 treatment caused rapid time- and dose-dependent increases in the steady state levels of PR mRNA, which peaked at 24 h (6-fold increase) and declined thereafter. All eight PR mRNA transcripts increased proportionally in response to E2. Immunoblot analyses indicated that these changes were accompanied by increases in PR protein (6-fold increase by 48 h), which continued to accumulate over time, unlike PR mRNA, which decreased despite continued E2 exposure. In contrast to the stimulatory effect of E2 on PR, the levels of immunoreactive estrogen receptor were reduced to about 15% of the control value by E2 within 48 h and remained low throughout the remaining treatment period. Treatment with P blocked the stimulatory effects of E2 on both PR mRNA and protein. These antagonistic actions of P were prevented by simultaneous administration of RU486. LY, which caused a slight (approximately 2.5-fold) increase in PR mRNA when administered alone, was an effective antagonist of E2-stimulated increases in PR mRNA. However, LY was incapable of completely antagonizing E2-stimulated increases in PR protein. The differences between the profiles of the time-dependent increases in PR mRNA and protein in response to E2, as well as the different sensitivities of these two end points to the antagonistic actions of LY, highlight the lack of direct correspondence between these two end points and suggest that E2 may be acting through distinct mechanisms (transcriptional and posttranscriptional, for example) to increase the levels of PR in the rat uterus. Our results indicate that E2 rapidly increases uterine PR expression and growth, and that P as well as sex steroid hormone antagonists are important modulators of these E2 actions in the rat uterus.


Factors associated with health-related quality of life among adults with tetralogy of Fallot.
Due to improved care, the numbers of patients with tetralogy of Fallot (ToF) are increasing. However, long-term morbidity and need for reinterventions are concerns and also address issues of quality of life (QoL). Patients with ToF and valid EuroQol-5 dimensions questionnaire (EQ-5D) were identified in the national Swedish register on congenital heart disease. EQ-5Dindex was calculated and dichotomised into best possible health-related QoL (EQ-5Dindex=1) or differed from 1. 288 patients met the criteria and were analysed. Univariate logistic regression showed a positive association between New York Heart Association (NYHA) class I (OR 8.32, 95% CI 3.80 to 18.21), physical activity >3 h/week (OR 3.34, 95% CI 1.67 to 6.66) and a better right ventricular function (OR 2.56, 95% CI 1.09 to 6.02). A negative association between symptoms (OR 0.23, 95% CI 0.13 to 0.42), cardiovascular medication (OR 0.31, 95% CI 0.18 to 0.53), age (OR 0.97, 95% CI 0.96 to 0.99) and EQ-5Dindex was observed. In multivariate logistic regression, NYHA I (OR 7.28, 95% CI 3.29 to 16.12) and physical activity >3 h/week (OR 2.27, 95% CI 1.07 to 4.84) remained associated with best possible health-related QoL. Replacing NYHA with symptoms in the model yielded similar results. In this registry study, self-reported physical activity, staff-reported NYHA class and absence of symptoms were strongly associated with best possible health-related QoL measured by EQ-5D. Physical activity level is a potential target for intervention to improve QoL in this population but randomised trials are needed to test such a hypothesis.


Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.
The etiology of multiple sclerosis (MS) is believed to involve environmental factors, but their identity and mode of action are unknown. In this study, we demonstrate that Ab specific for the extracellular Ig-like domain of myelin oligodendrocyte glycoprotein (MOG) cross-reacts with a homologous N-terminal domain of the bovine milk protein butyrophilin (BTN). Analysis of paired samples of MS sera and cerebrospinal fluid (CSF) identified a BTN-specific Ab response in the CNS that differed in its epitope specificity from that in the periphery. This effect was statistically significant for the Ab response to BTN(76-100) (p = 0.0026), which cosequestered in the CSF compartment with Ab to the homologous MOG peptide MOG(76-100) in 34% of MS patients (n = 35). These observations suggested that intratheccal synthesis of Ab recognizing BTN peptide epitopes in the CNS was sustained by molecular mimicry with MOG. Formal evidence of molecular mimicry between the two proteins was obtained by analyzing MOG-specific autoantibodies immunopurified from MS sera. The MOG-specific Ab repertoire cross-reacts with multiple BTN peptide epitopes including a MOG/BTN(76-100)-specific component that occurred at a higher frequency in MS patients than in seropositive healthy controls, as well as responses to epitopes within MOG/BTN(1-39) that occur at similar frequencies in both groups. The demonstration of molecular mimicry between MOG and BTN, along with sequestration of BTN-reactive Ab in CSF suggests that exposure to this common dietary Ag may influence the composition and function of the MOG-specific autoimmune repertoire during the course of MS.


Parallel adaptations and common host cell responses enabling feeding of obligate and facultative plant parasitic nematodes.
Parallel adaptations enabling the use of plant cells as the primary food source have occurred multiple times in distinct nematode clades. The hallmark of all extant obligate and facultative plant-feeding nematodes is the presence of an oral stylet, which is required for penetration of plant cell walls, delivery of pharyngeal gland secretions into host cells and selective uptake of plant assimilates. Plant parasites from different clades, and even within a single clade, display a large diversity in feeding behaviours ranging from short feeding cycles on single cells to prolonged feeding on highly sophisticated host cell complexes. Despite these differences, feeding of nematodes frequently (but certainly not always) induces common responses in host cells (e.g. endopolyploidization and cellular hypertrophy). It is thought that these host cell responses are brought about by the interplay of effectors and other biological active compounds in stylet secretions of feeding nematodes, but this has only been studied for the most advanced sedentary plant parasites. In fact, these responses are thought to be fundamental for prolonged feeding of sedentary plant parasites on host cells. However, as we discuss in this review, some of these common plant responses to independent lineages of plant parasitic nematodes might also be generic reactions to cell stress and as such their onset may not require specific inputs from plant parasitic nematodes. Sedentary plant parasitic nematodes may utilize effectors and their ability to synthesize other biologically active compounds to tailor these common responses for prolonged feeding on host cells.


Vocal Biomarker Is Associated With Hospitalization and Mortality Among Heart Failure Patients.
Background The purpose of this article is to evaluate the association of voice signal analysis with adverse outcome among patients with congestive heart failure (CHF). Methods and Results The study cohort included 10 583 patients who were registered to a call center of patients who had chronic conditions including CHF in Israel between 2013 and 2018. A total of 223 acoustic features were extracted from 20 s of speech for each patient. A biomarker was developed based on a training cohort of non-CHF patients (N=8316). The biomarker was tested on a mutually exclusive CHF study cohort (N=2267) and was evaluated as a continuous and ordinal (4 quartiles) variable. Median age of the CHF study population was 77 (interquartile range 68-83) and 63% were men. During a median follow-up of 20 months (interquartile range 9-34), 824 (36%) patients died. Kaplan-Meier survival analysis showed higher cumulative probability of death with increasing quartiles (23%, 29%, 38%, and 54%; P<0.001). Survival analysis with adjustment to known predictors of poor survival demonstrated that each SD increase in the biomarker was associated with a significant 32% increased risk of death during follow-up (95% CI, 1.24-1.41, P<0.001) and that compared with the lowest quartile, patients in the highest quartile were 96% more likely to die (95% CI, 1.59-2.42, P<0.001). The model consistently demonstrated an independent association of the biomarker with hospitalizations during follow-up (P<0.001). Conclusions Noninvasive vocal biomarker is associated with adverse outcome among CHF patients, suggesting a possible role for voice analysis in telemedicine and CHF patient care.


Sexual dimorphism in the glucose homeostasis phenotype of the Aromatase Knockout (ArKO) mice.
We investigated the effects of estrogens on glucose homeostasis using the Aromatase Knockout (ArKO) mouse, which is unable to convert androgens into estrogens. The ArKO mouse is a model of total estrogen ablation which develops symptoms of metabolic syndrome. To determine the development and progression of whole body state of insulin resistance of ArKO mice, comprehensive whole body tolerance tests were performed on WT, ArKO and estrogen administrated mice at 3 and 12 months of age. The absence of estrogens in the male ArKO mice leads to hepatic insulin resistance, glucose and pyruvate intolerance from 3 to 12 months with consistent improvement upon estrogen treatment. Estrogen absence in the female ArKO mice leads to glucose intolerance without pyruvate intolerance or insulin resistance. The replacement of estrogens in the female WT and ArKO mice exhibited both insulin sensitizing and resistance effects depending on age and dosage. In conclusion, this study presents information on the sexually dimorphic roles of estrogens on glucose homeostasis regulation.


Fast-GBS: a new pipeline for the efficient and highly accurate calling of SNPs from genotyping-by-sequencing data.
Next-generation sequencing (NGS) technologies have accelerated considerably the investigation into the composition of genomes and their functions. Genotyping-by-sequencing (GBS) is a genotyping approach that makes use of NGS to rapidly and economically scan a genome. It has been shown to allow the simultaneous discovery and genotyping of thousands to millions of SNPs across a wide range of species. For most users, the main challenge in GBS is the bioinformatics analysis of the large amount of sequence information derived from sequencing GBS libraries in view of calling alleles at SNP loci. Herein we describe a new GBS bioinformatics pipeline, Fast-GBS, designed to provide highly accurate genotyping, to require modest computing resources and to offer ease of use. Fast-GBS is built upon standard bioinformatics language and file formats, is capable of handling data from different sequencing platforms, is capable of detecting different kinds of variants (SNPs, MNPs, and Indels). To illustrate its performance, we called variants in three collections of samples (soybean, barley, and potato) that cover a range of different genome sizes, levels of genome complexity, and ploidy. Within these small sets of samples, we called 35 k, 32 k and 38 k SNPs for soybean, barley and potato, respectively. To assess genotype accuracy, we compared these GBS-derived SNP genotypes with independent data sets obtained from whole-genome sequencing or SNP arrays. This analysis yielded estimated accuracies of 98.7, 95.2, and 94% for soybean, barley, and potato, respectively. We conclude that Fast-GBS provides a highly efficient and reliable tool for calling SNPs from GBS data.


The planarian regeneration transcriptome reveals a shared but temporally shifted regulatory program between opposing head and tail scenarios.
Planarians can regenerate entire animals from a small fragment of the body. The regenerating fragment is able to create new tissues and remodel existing tissues to form a complete animal. Thus different fragments with very different starting components eventually converge on the same solution. In this study, we performed an extensive RNA-seq time-course on regenerating head and tail fragments to observe the differences and similarities of the transcriptional landscape between head and tail fragments during regeneration. We have consolidated existing transcriptomic data for S. mediterranea to generate a high confidence set of transcripts for use in genome wide expression studies. We performed a RNA-seq time-course on regenerating head and tail fragments from 0 hours to 3 days. We found that the transcriptome profiles of head and tail regeneration were very different at the start of regeneration; however, an unexpected convergence of transcriptional profiles occurred at 48 hours when head and tail fragments are still morphologically distinct. By comparing differentially expressed transcripts at various time-points, we revealed that this divergence/convergence pattern is caused by a shared regulatory program that runs early in heads and later in tails.Additionally, we also performed RNA-seq on smed-prep(RNAi) tail fragments which ultimately fail to regenerate anterior structures. We find the gene regulation program in response to smed-prep(RNAi) to display the opposite regulatory trend compared to the previously mentioned share regulatory program during regeneration. Using annotation data and comparative approaches, we also identified a set of approximately 4,800 triclad specific transcripts that were enriched amongst the genes displaying differential expression during the regeneration time-course. The regeneration transcriptome of head and tail regeneration provides us with a rich resource for investigating the global expression changes that occurs during regeneration. We show that very different regenerative scenarios utilize a shared core regenerative program. Furthermore, our consolidated transcriptome and annotations allowed us to identity triclad specific transcripts that are enriched within this core regulatory program. Our data support the hypothesis that both conserved aspects of animal developmental programs and recent evolutionarily innovations work in concert to control regeneration.


Metabolic response to provision of mixed protein-carbohydrate supplementation during endurance exercise.
The interaction of substrates and hormones in response to ingestion of intact proteins during endurance exercise is unknown. This study characterized substrate and hormone responses to supplementation during endurance exercise. Nine male runners participated in 3 trials in which a non-fat (MILK), carbohydrate (CHO), or placebo (PLA) drink was consumed during a 2-hour treadmill run at 65% VO2max. Circulating levels of insulin, glucagon, epinephrine, norepinephrine, growth hormone, testosterone, and cortisol were measured. Plasma substrates included glucose, lactate, free fatty acids, and select amino acids. Except for insulin and cortisol, hormones increased with exercise. While post-exercise insulin concentrations declined similarly in all 3 trials, the glucagon increase was greatest following MILK consumption. CHO blunted the post-exercise increase in growth hormone compared to levels in MILK. Free fatty acids and plasma amino acids also were responsive to nutritional supplementation with both CHO and MILK attenuating the rise in free fatty acids compared to the increase observed in PLA. Correspondingly, respiratory exchange ratio increased during CHO. Essential amino acids increased significantly only after MILK and were either unchanged or decreased in CHO. PLA was characterized by a decrease in branched-chain amino acid concentrations. Modest nutritional supplementation in this study altered the endocrine response as well as substrate availability and utilization following and during an endurance run, respectively.


Impact of neoadjuvant treatment on total mesorectal excision for ultra-low rectal cancers.
This study reviewed the impact of pre-operative chemoradiotherapy or post-operative chemotherapy and/or radiotherapy on total mesorectal excision (TME) for ultralow rectal cancers that required either low anterior resection with peranal coloanal anastomosis or abdomino-perineal resection (APR). We examined surgical complications, local recurrence and survival. Of the 1270 patients who underwent radical resection for rectal cancer from 1994 till 2007, 180 with tumors within 4 cm with either peranal coloanal anastomosis or APR were analyzed. Patients were compared in groups that had surgery only (Group A), pre-operative chemoradiotherapy (Group B), and post-operative therapy (Group C). There were 115 males and the mean age was 65.43 years (range 30-89). APR was performed in 134 patients while 46 had a sphincter-preserving resection with peranal coloanal anastomosis. The mean follow-up period was 52.98 months (range: 0.57 to 178.9). There were 69, 58 and 53 patients in Groups A, B, and C, respectively. Nine patients in Group B could go on to have sphincter-saving rectal resection. The overall peri-operative complication rate was 43.4% in Group A vs. 29.3% in Group B vs. 39.6% in Group C, respectively. The local recurrence rate was significantly lower in Group B (8.6.9% vs. 21.7% in Group A vs. 33.9% in Group C) p < 0.05. The 5-year cancer-specific survival rates for Group A was 49.3%, Group B was 69.9% and Group C was 38.8% (p = 0.14). Pre-operative chemoradiation in low rectal cancer is not associated with a higher incidence of peri-operative complications and its benefits may include reduction local recurrence.


Elevated Postvoid Residual Urine Volume: Identifying Risk Factors and Predicting Resolution in Women With Pelvic Organ Prolapse.
This study aims to identify risk factors for elevated preoperative postvoid residual (PVR) and persistently elevated postoperative PVR and to evaluate the resolution rate of elevated PVR urine volume in patients undergoing reconstructive surgery for pelvic organ prolapse (POP). This was a retrospective cohort study comparing 50 women with elevated preoperative PVR (≥100 mL) and 50 women with normal PVR (<100 mL). Preoperative demographic, physical examination, urodynamic data, type of surgery performed, and postoperative trial of void data were collected. Variables were evaluated for association with elevated PVR using Student t test or Mann-Whitney U test, and χ or Fisher exact test. The elevated PVR cohort was older (65.5 ± 13.3 vs 60.6 ± 10.1 years, P = 0.04). The cohorts did not differ by body mass index, parity, number of cesarean deliveries, prior hysterectomy, incontinence, prolapse surgery, menopausal status, hormone replacement therapy, history of recurrent urinary tract infections, diabetes mellitus, or maximum bladder capacity. Most patients had preoperative anterior prolapse stage 2 or 3. Complaints of incontinence, incomplete bladder emptying, and overactive bladder did not differ between groups. Performed Surgical procedures, cystoscopy findings, and rate of postoperative trial of void failures did not differ between groups. One patient per cohort learned clean intermittent self-catheterization for persistently elevated PVR. All women undergoing surgery for POP had postoperative resolution of elevated PVR. Patients with nonneurogenic-elevated PVR can be reassured that bladder emptying will improve after surgical repair of POP.


Phase I clinical studies of antineoplaston A5 injections.
Antineoplaston A5 is a mixture of small peptides and amino acid derivatives isolated from human urine which show a unique pattern of growth inhibition in the tissue culture of human neoplastic cells and no significant animal toxicity. Clinical trials described in this paper involved 15 patients diagnosed with advanced neoplastic diseases. The patients' diagnoses included: lung cancer, stage III (4 cases); breast, stages III and IV (3); colorectal, stage IV (2); bladder (2); and single cases of adenocarcinoma of the jejunum, stage IV; adenocarcinoma of the prostate, stage IV; adenocarcinoma of the ovary, stage IV and astrocytoma, grade IV. Antineoplaston A5 was administered daily in divided doses intravenously through a subclavian vein catheter. The formulation was given from 47 to 130 days. The highest dosage attained was 153 mg/kg/24 h. Adverse effects included febrile reaction in five patients, arthralgia in one patient and premature beats and pressure in the chest in one patient. The side-effects were very mild and usually experienced only once during the entire course of treatment. Desirable side-effects included increase of platelet count, increase of white blood cell count and hypertrophy of epidermis. Nine patients (60%) had objective response to the treatment. They were diagnosed with cancer of the lung (3 patients), breast (2), colorectal (2) and bladder (2). Four patients had increasing disease and two patients were classified as having stable disease without objective improvement.


Density field theory approach to design multi-template imprinted polymers for carcinogenic PAHs sensing.
Molecular imprinting is an interesting technique for preparation of molecular recognition materials with discriminating similar molecules from complex systems. In particular, imprinting more than one molecule has immense application in remediation of industrial waste. Major difficulty in molecular imprinting is the selection of suitable polymer precursors. In this article, authors have proposed a new computational approach for combinatorial screening of polymer precursor library to select appropriate polymer precursors to prepare imprinted polymer capable of selectively binding carcinogenic polycyclic aromatic hydrocarbons (PAHs). Molecular Dynamics (MD) and Quantum Mechanics (QM) models were used to compute interaction energy scores between polymer precursors and PAHs in a simulated solvent box. A self-designed virtual library of functional monomers has been prepared, and then used for MD simulations to screen the best functional monomers. Initially, molecules used in the study were geometrically optimized and then interaction energies were computed using density functional theory (DFT) in Becke 3-Parameter Exchange Correlation Function (B3LYP) level with 6-31G*basis set on Gaussian 4.1 Ver. software. Complimentary to theoretical predictions, selected polymers were prepared in laboratory and compared theoretically computed binding score with the binding capacity of the polymer on spectrofluorimetry. The computer simulations used in this research paper are rapid and reliable for the combinatorial screening of polymer precursors in experimental-free way to design of multi-template imprinted polymers.


Digitalis for treatment of congestive heart failure in patients in sinus rhythm.
Digitalis glycosides have been in clinical use in the treatment of congestive heart failure for more than 200 years. In recent years several trials have been conducted to address concerns about efficacy and toxicity. Although a systematic review of the literature was recently published, an update is required to include more current trials. To examine the effectiveness of digitalis glycosides in treating congestive heart failure in patients with normal sinus rhythm. To examine the effect of digitalis in patients taking diuretics, angiotensin converting enzyme (ACE) inhibitors, and beta blockers; patients with varying severity and duration of disease; patients with prior exposure to digitalis vs. no prior exposure; and patients with diastolic vs. systolic dysfunction. Electronic databases were searched between 1966 and 2000. Dissertation Abstracts and annual meeting abstracts of the American Heart Association, American College of Cardiology, and European Society of Cardiology were searched from 1996-2000. In addition, reference lists provided by the pharmaceutical industry (Glaxo Wellcome Inc.) were searched. Included were randomized placebo-controlled trials of 20 or more adult patients of either sex with symptomatic congestive heart failure who were studied for seven weeks or more. Excluded were trials in which the prevalence of atrial fibrillation was 2% or greater, or in which any arrhythmia that might compromise cardiac function or any potentially reversible cause of heart failure such as acute ischemic heart disease or myocarditis was present. Articles selected from the searches described above were reviewed by one of the coauthors, and validated by staff from the central office of the Heart Collaborative Review Group in Bristol, UK. Eleven articles meeting the defined criteria were identified, and major endpoints of mortality, hospitalization, and clinical status, based respectively upon 8, 4, and 10 of these selected studies, were recorded and analyzed. The data show that there is no difference in mortality between treatment and control groups, whereas digitalis therapy is associated with a lower rate of hospitalization and of clinical deterioration. The literature indicates that digitalis has a useful role in the treatment of patients with congestive heart failure who are in normal sinus rhythm.


Surgeon-Therapist Communication: Do All Members See Eye-to-Eye?
Poor interprofessional collaboration has been shown to negatively affect patient care within many fields of medicine. Growing evidence is suggesting that improved interprofessional collaboration can positively affect patient care. Postoperative rehabilitation of many orthopedic conditions necessitates the combined efforts of surgeons, and therapists. There is a paucity of literature examining collaboration among orthopedic surgeons and therapists regarding postoperative rehabilitation. The following study examines the perceived quality of communications between orthopedic surgeons and therapists employing an online survey. We hypothesized that collaborative practice patterns result in improved perceptions of communication. Ethics board approval was obtained. Subjects consisted of orthopedic surgeons, licensed physiotherapists and certified athletic therapists. The online survey was distributed through the Canadian Orthopaedic Association (COA), the Canadian Physiotherapy Association (CPA) and the Canadian Athletic Therapists Association (CATA). Data analysis was performed using Stata/IC 12.1 (Stata Corp, College Station, TX, USA). Descriptive statistics were calculated to determine the median responses and ranges. Median responses were compared using the Kruskal-Wallis one-way analysis of variance. Qualitative analysis regarding text responses was performed by three reviewers. Responses were received from all specialties (COA 164, CPA 524, CATA 163). There were significant differences in the perceived quality of communication by quantitative and qualitative analysis (p < 0.001). Analysis of communication within practice patterns of stand-alone versus collaborative revealed improved perception of communication quality with increased contact. 65.6% of responders that practiced as stand-alone had a negative view of interprofessional communication. 48.4% of responders in a collaborative practice had a positive view of interprofessional communication. Analysis of the preferred form of communication found that orthopedic surgeons felt the most useful referral information was a pre-printed consult sheet (odds ratio [OR] = 1.56, p < 0.001), whereas therapists were more likely to rank consult notes (OR = 1.27, p < 0.042) and operative reports (OR = 1.20, p < 0.092) as a more useful form of communication. Collaborative practice shows improved perceptions of communication between specialties. Orthopedic surgeons perceive a higher quality of communication than therapists. Therapists and orthopedic surgeons also do not agree on the information that should be relayed between the specialties regarding postoperative rehabilitation.


Branch retinal artery occlusion after septoplasty.
Loss of vision after uncomplicated rhinosurgery is a rare and uncommon complication. The authors describe a case of branch retinal artery occlusion after septoplasty in a 40-year-old otherwise healthy man. The likely etiology was injection of local anesthetics into the nasal mucosa during surgery. Vision loss could potentially have been prevented through the application of topical vasoconstrictive agents prior to anesthetic injection. Furthermore, slow injection and aspiration prior to injection could also help prevent inadvertent intraarterial injection.


Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98.
We report the long-term results of a randomized clinical trial comparing induction therapy with once per week for 4 weeks single-agent rituximab alone versus induction followed by 4 cycles of maintenance therapy every 2 months in patients with follicular lymphoma. Patients (prior chemotherapy 138; chemotherapy-naive 64) received single-agent rituximab and if nonprogressive, were randomly assigned to no further treatment (observation) or four additional doses of rituximab given at 2-month intervals (prolonged exposure). At a median follow-up of 9.5 years and with all living patients having been observed for at least 5 years, the median event-free survival (EFS) was 13 months for the observation and 24 months for the prolonged exposure arm (P < .001). In the observation arm, patients without events at 8 years were 5%, while in the prolonged exposure arm they were 27%. Of previously untreated patients receiving prolonged treatment after responding to rituximab induction, at 8 years 45% were still without event. The only favorable prognostic factor for EFS in a multivariate Cox regression was the prolonged rituximab schedule (hazard ratio, 0.59; 95% CI, 0.39 to 0.88; P = .009), whereas being chemotherapy naive, presenting with stage lower than IV, and showing a VV phenotype at position 158 of the Fc-gamma RIIIA receptor were not of independent prognostic value. No long-term toxicity potentially due to rituximab was observed. An important proportion of patients experienced long-term remission after prolonged exposure to rituximab, particularly if they had no prior treatment and responded to rituximab induction.


Visual word ambiguity.
This paper studies automatic image classification by modeling soft assignment in the popular codebook model. The codebook model describes an image as a bag of discrete visual words selected from a vocabulary, where the frequency distributions of visual words in an image allow classification. One inherent component of the codebook model is the assignment of discrete visual words to continuous image features. Despite the clear mismatch of this hard assignment with the nature of continuous features, the approach has been successfully applied for some years. In this paper, we investigate four types of soft assignment of visual words to image features. We demonstrate that explicitly modeling visual word assignment ambiguity improves classification performance compared to the hard assignment of the traditional codebook model. The traditional codebook model is compared against our method for five well-known data sets: 15 natural scenes, Caltech-101, Caltech-256, and Pascal VOC 2007/2008. We demonstrate that large codebook vocabulary sizes completely deteriorate the performance of the traditional model, whereas the proposed model performs consistently. Moreover, we show that our method profits in high-dimensional feature spaces and reaps higher benefits when increasing the number of image categories.


Filter-Aided Sample Preparation Procedure for Mass Spectrometric Analysis of Plant Histones.
Characterization of histone post-translational modifications (PTMs) is still challenging, and robust histone sample preparation is essential for convincing evaluation of PTMs by mass spectrometry. An effective protocol for extracting plant histone proteins must also avoid excessive co-extraction of the numerous potential interfering compounds, including those related to secondary metabolism. Currently, the co-existence of histone marks is addressed mostly by shotgun proteomic analysis following chemical derivatization of histone lysine residues. Here, we report a straightforward approach for plant histone sample preparation for mass spectrometry, based on filter-aided sample preparation coupled with histone propionylation. The approach offers savings in sample handling and preparation time, enables removal of interfering compounds from the sample, and does not require either precipitation or dialysis of histone extract. We show the comparison of two protocol variants for derivatization of histone proteins, in-solution propionylation in the vial and propionylation on the filter unit. For both protocols, we obtained identical abundances of post-translationally modified histone peptides. Although shorter time is required for histone protein labeling on the filter unit, in-solution derivatization slightly outweighed filter-based variant by lower data variability. Nevertheless, both protocol variants appear to be efficient and convenient approach for preparation of plant histones for mass spectrometric analysis.


Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome.
Dorsal-ventral limb patterning in vertebrates is thought to be controlled by the LIM-homeodomain protein Lmx1b which is expressed in a spatially and temporally restricted manner along the dorsal-ventral limb axis. Here we describe the phenotype resulting from targeted disruption of Lmx1b. Our results demonstrate that Lmx1b is essential for the specification of dorsal limb fates at both the zeugopodal and autopodal level with prominent phenotypes including an absence of nails and patellae. These features are similar to those present in a dominantly inherited human condition called nail patella syndrome (NPS), which also has renal involvement. Mouse Lmx1b maps to a region syntenic to that of the NPS gene, and kidneys of Lmx1b mutant mice exhibit pathological changes similar to that observed in NPS (refs 5,6). Our results demonstrate an essential function for Lmx1b in mouse limb and kidney development and suggest that NPS might result from mutations in the human LMX1B gene.


Potential of dopamine A-1 agonists in the management of acute renal failure.
Many therapeutic approaches have been undertaken both to prevent acute ischemic or nephrotoxic renal injury and, once acute renal failure (ARF) has developed, to improve renal function and reduce mortality. To date, most therapeutic studies have investigated the effects of diuretics (eg, mannitol, furosemide), vasoactive agents (calcium channel blockers, atrial natriuretic peptide), or dopamine (a nonselective dopaminergic agent [DAA]) in one or more phases of ARF. Unfortunately, studies of the use of DAA in ARF are complicated by the existence of at least two different DAA receptors (DA-1 and DA-2), and by the stimulation of alpha- and/or beta-adrenergic receptors by high doses of DAA. The undesirable side effects of high doses of dopamine and the inconclusive results using low doses (ie, "renal doses") of dopamine (a nonselective DAA) have prompted consideration of the use of more selective dopaminergic agonists for the prophylaxis and treatment of ARF. Selective DA-1 agonists exhibit many desirable renal effects that theoretically support their use for the prophylaxis and/or treatment of ARF, including decreases in renal vascular resistance accompanied by increases in renal blood flow and glomerular filtration rate, and increases in sodium excretion and urine volume. Even at high doses, some selective DA-1 agonists, such as fenoldopam, do not stimulate DA-2 receptors, or adrenergic alpha- or beta-receptors, and thus are free of unwanted side effects (eg, arrhythmias). Results of several studies in normal and hypertensive humans, and a few studies in animal models, are consistent with the notion that DA-1 agonists may be useful in preventing or treating ARF. Careful randomized prospective clinical trials of DA-1 agonists in human ARF are needed to test this hypothesis.


Prevalence of methicillin-resistant Staphylococcus aureus nasal carriage among hospitalised patients with tuberculosis in rural Kwazulu-Natal.
There is little information regarding the presence and characteristics of methicillin-resistant Staphylococcus aureus (MRSA), an important nosocomial pathogen, in rural African hospitals. To determine the prevalence of MRSA colonisation in patients admitted to a rural hospital with tuberculosis (TB) in an endemic HIV area and to describe transmission dynamics and resistance patterns among MRSA isolates. A prospective prevalence survey in the adult TB wards of the Church of Scotland Hospital, a provincial government district hospital in Tugela Ferry, KwaZulu-Natal. Patients were eligible if over the age of 15 and admitted to the TB wards between 15 November and 15 December 2008. Nasal swabs were cultured within 24 hours of admission and repeated at hospital-day 14 or upon discharge. Susceptibility testing was performed with standard disk diffusion. Demographic and clinical information was extracted from medical charts. Of 52 patients with an admission nasal swab, 11 (21%) were positive for MRSA. An additional 4 (10%) of patients with negative admission swabs were positive for MRSA on repeat testing. MRSA carriage on admission was more common among patients with previous hospitalisation, and among HIV-infected patients was significantly associated with lower CD4 counts (p = 0.03). All MRSA isolates were resistant to cotrimoxazole, and 74% were resistant to > 5 dclasses of antibiotics; all retained susceptibility to vancomycin. A high prevalence of multidrug-resistant MRSA nasal carriage was found. Studies are needed to validate nosocomial acquisition and to evaluate the impact of MRSA on morbidity and mortality among TB patients in similar settings.


Prevalence and persistent use of psychotropic drugs in older adults receiving domiciliary care at baseline.
Little is known about the use of psychotropic drugs in older adults receiving domiciliary care. The first aim was to describe the prevalence and persistency of use of psychotropic drugs in older adults (≥ 70 years) with and without dementia receiving domiciliary care. Furthermore, the second aim was to explore factors associated with persistent drug use at two consecutive time-points. Lastly, we aimed to examine if use of psychotropic drugs changed after admission to a nursing home. In total, 1001 community-dwelling older adults receiving domiciliary care at inclusion participated in the study. Information about psychotropic drug use was collected at baseline, after 18 months and after 36 months. The participants' cognitive function, neuropsychiatric symptoms (NPS) and physical health were assessed at the same assessments. Participants were evaluated for dementia based on all gathered information. Formal level of care (domiciliary care or in a nursing home) was registered at the follow-up assessments. Prevalence and persistent use of psychotropic drugs in older adults receiving domiciliary care was high. Participants with dementia more often used antipsychotics and antidepressants than participants without dementia. The majority of the participants using antipsychotic drugs used traditional antipsychotics. Younger age was associated with higher odds for persistent use of antipsychotics and antidepressants, and lower odds for persistent use of sedatives. Severity of NPS was associated with persistent use of antidepressants. The odds for use of antipsychotics and antidepressants were higher in those admitted to a nursing home as compared to the community-dwelling participants at the last follow-up. There was a high prevalence and persistency of use of psychotropic drugs. The prevalence of use of traditional antipsychotics was surprisingly high, which is alarming. Monitoring the effect and adverse effects of psychotropic drugs is an important part of the treatment, and discontinuation should be considered when possible due to the odds for severe adverse effects of such drugs in people with dementia.


Milnacipran: beyond a role of antidepressant.
Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI) with negligible effects on any presynaptic or postsynaptic receptors. Milnacipran has unique pharmacokinetic and pharmacodynamic characteristics that distinguish it from the other marketed serotonin and norepinephrine reuptake inhibitors, venlafaxine, desvenlafaxine, and duloxetine such as equipotent serotonin and norepinephrine reuptake inhibition and a linear dose-concentration trend at therapeutic doses. The half-life of milnacipran is approximately 8 hours. In addition, milnacipran does not inhibit the cytochrome P 450 system, indicating minimal propensity for drug-drug interactions. The antidepressant efficacy of milnacipran has been clearly established in a number of randomized, double-blind, placebo-controlled clinical trials, and it has been widely used for treating major depressive disorder. Moreover, evidence suggests that milnacipran is effective and tolerable in the treatment of fibromyalgia and may have usefulness for fatigue and anxiety symptoms. The current paper reviews researches conducted to date that is relevant to the efficacy, tolerability, and mechanism of action of milnacipran in the treatment of depression, fibromyalgia, and other psychiatric syndromes. Future directions of research are also identified.