Health professionals' perception of appropriateness of care: a qualitative study in Italian pediatric hospices.
Appropriateness is particularly relevant in palliative care, an area in which it is essential to question the real need for treatments. Few studies explored the perception of appropriateness by professionals in pediatric palliative care, revealing the conflict sometimes faced when confronted with the uncertainty of prognosis and end-of-life decisions. The objective of this study is firstly to investigate the perception that doctors, nurses and psychologists, operating in Italian pediatric hospices, have of the appropriateness of the care they provide. Secondly, to understand what repercussions the perception of non-appropriateness has at individual and team level. A qualitative study was conducted between 2019 and 2020 through semi-structured interviews with a convenience sample of 17 professionals working it Italian pediatric hospices. The interviewees do not refer to a common concept of appropriateness, but compare the latter to: the quality of life, the global care of the assisted person, the proportionality of care, the early recognition of the need for palliative care. The discussion within the team emerges as a privileged place to manage the discomfort of individual professionals in the face of treatment choices in conflict with their own values. the non-referring to a univocal conception of appropriateness deprives professionals of an objective criterion to resolve the most difficult decisions. However, it allows them to establish what from time to time seems to be the most appropriate care pathway for a given patient, at a given time and context, preserving the goal of personalized care.


Broadening the horizon: potential applications of CAR-T cells beyond current indications.
Engineering immune cells to treat hematological malignancies has been a major focus of research since the first resounding successes of CAR-T-cell therapies in B-ALL. Several diseases can now be treated in highly therapy-refractory or relapsed conditions. Currently, a number of CD19- or BCMA-specific CAR-T-cell therapies are approved for acute lymphoblastic leukemia (ALL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), multiple myeloma (MM), and follicular lymphoma (FL). The implementation of these therapies has significantly improved patient outcome and survival even in cases with previously very poor prognosis. In this comprehensive review, we present the current state of research, recent innovations, and the applications of CAR-T-cell therapy in a selected group of hematologic malignancies. We focus on B- and T-cell malignancies, including the entities of cutaneous and peripheral T-cell lymphoma (T-ALL, PTCL, CTCL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), classical Hodgkin-Lymphoma (HL), Burkitt-Lymphoma (BL), hairy cell leukemia (HCL), and Waldenström's macroglobulinemia (WM). While these diseases are highly heterogenous, we highlight several similarly used approaches (combination with established therapeutics, target depletion on healthy cells), targets used in multiple diseases (CD30, CD38, TRBC1/2), and unique features that require individualized approaches. Furthermore, we focus on current limitations of CAR-T-cell therapy in individual diseases and entities such as immunocompromising tumor microenvironment (TME), risk of on-target-off-tumor effects, and differences in the occurrence of adverse events. Finally, we present an outlook into novel innovations in CAR-T-cell engineering like the use of artificial intelligence and the future role of CAR-T cells in therapy regimens in everyday clinical practice.


Life histories as mosaics: Plastic and genetic components differ among traits that underpin life-history strategies.
Life-history phenotypes emerge from clusters of traits that are the product of genes and phenotypic plasticity. If the impact of the environment differs substantially between traits, then life histories might not evolve as a cohesive whole. We quantified the sensitivity of components of the life history to food availability, a key environmental difference in the habitat occupied by contrasting ecotypes, for 36 traits in fast- and slow-reproducing Trinidadian guppies. Our dataset included six putatively independent origins of the slow-reproducing, derived ecotype. Traits varied substantially in plastic and genetic control. Twelve traits were influenced only by food availability (body lengths, body weights), five only by genetic differentiation (interbirth intervals, offspring sizes), 10 by both (litter sizes, reproductive timing), and nine by neither (fat contents, reproductive allotment). Ecotype-by-food interactions were negligible. The response to low food was aligned with the genetic difference between high- and low-food environments, suggesting that plasticity was adaptive. The heterogeneity among traits in environmental sensitivity and genetic differentiation reveals that the components of the life history may not evolve in concert. Ecotypes may instead represent mosaics of trait groups that differ in their rate of evolution.


Cardiac Overexpression of PDE4B Blunts β-Adrenergic Response and Maladaptive Remodeling in Heart Failure.
The cyclic AMP (adenosine monophosphate; cAMP)-hydrolyzing protein PDE4B (phosphodiesterase 4B) is a key negative regulator of cardiac β-adrenergic receptor stimulation. PDE4B deficiency leads to abnormal Ca2+ handling and PDE4B is decreased in pressure overload hypertrophy, suggesting that increasing PDE4B in the heart is beneficial in heart failure. We measured PDE4B expression in human cardiac tissues and developed 2 transgenic mouse lines with cardiomyocyte-specific overexpression of PDE4B and an adeno-associated virus serotype 9 encoding PDE4B. Myocardial structure and function were evaluated by echocardiography, ECG, and in Langendorff-perfused hearts. Also, cAMP and PKA (cAMP dependent protein kinase) activity were monitored by Förster resonance energy transfer, L-type Ca2+ current by whole-cell patch-clamp, and cardiomyocyte shortening and Ca2+ transients with an Ionoptix system. Heart failure was induced by 2 weeks infusion of isoproterenol or transverse aortic constriction. Cardiac remodeling was evaluated by serial echocardiography, morphometric analysis, and histology. PDE4B protein was decreased in human failing hearts. The first PDE4B-transgenic mouse line (TG15) had a ≈15-fold increase in cardiac cAMP-PDE activity and a ≈30% decrease in cAMP content and fractional shortening associated with a mild cardiac hypertrophy that resorbed with age. Basal ex vivo myocardial function was unchanged, but β-adrenergic receptor stimulation of cardiac inotropy, cAMP, PKA, L-type Ca2+ current, Ca2+ transients, and cell contraction were blunted. Endurance capacity and life expectancy were normal. Moreover, these mice were protected from systolic dysfunction, hypertrophy, lung congestion, and fibrosis induced by chronic isoproterenol treatment. In the second PDE4B-transgenic mouse line (TG50), markedly higher PDE4B overexpression, resulting in a ≈50-fold increase in cardiac cAMP-PDE activity caused a ≈50% decrease in fractional shortening, hypertrophy, dilatation, and premature death. In contrast, mice injected with adeno-associated virus serotype 9 encoding PDE4B (1012 viral particles/mouse) had a ≈50% increase in cardiac cAMP-PDE activity, which did not modify basal cardiac function but efficiently prevented systolic dysfunction, apoptosis, and fibrosis, while attenuating hypertrophy induced by chronic isoproterenol infusion. Similarly, adeno-associated virus serotype 9 encoding PDE4B slowed contractile deterioration, attenuated hypertrophy and lung congestion, and prevented apoptosis and fibrotic remodeling in transverse aortic constriction. Our results indicate that a moderate increase in PDE4B is cardioprotective and suggest that cardiac gene therapy with PDE4B might constitute a new promising approach to treat heart failure.


Dissemination of Imidacloprid Through Dairy Cattle Manure and Its Effect on the Biological Control Agent, Spalangia endius (Hymenoptera: Pteromalidae), and a Filth Fly Host, Musca domestica (Diptera: Muscidae).
Filth flies, including house flies, Musca domestica L., develop in animal manure. Adult house flies often are controlled with pesticides such as imidacloprid. How imidacloprid disseminates and persists after it contaminates manure was measured at a dairy farm. A week after application of imidacloprid via fly bait to cattle manure, a mean of approximately 4 ppm of imidacloprid, and as high as 15 ppm, was quantifiable up to 12 cm from the application site, but not farther. Laboratory experiments addressed the impact of 15 ppm of imidacloprid in manure on egg-to-adult development of house flies and on the biological control ability of a house fly pupal parasitoid, Spalangia endius Walker. In uncontaminated manure, 93% of eggs developed to adults, versus 7% in contaminated manure. In the parasitoid experiment, fly pupae were placed in contaminated or uncontaminated manure with or without S. endius. In the absence of S. endius, nearly 100% of flies emerged, with or without imidacloprid. In the presence of S. endius, only 11% of flies emerged from uncontaminated manure, versus 36% from contaminated manure; and parasitoids emerged from 82% of hosts in uncontaminated manure versus 53% in contaminated manure. These results suggest that realistic concentrations of imidacloprid in filth fly breeding habitat may interfere with house flies developing to the pupal stage, but also with parasitoids locating and utilizing house flies. However, after 1 wk, the effects on parasitoids will be low 12 cm beyond where bait was applied.


Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle: implications for exercise hyperemia.
During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However, interstitial ATP has solely been described to induce vasoconstriction in skeletal muscle. To examine whether interstitial ATP induces vasodilation in skeletal muscle and to what extent this vasoactive effect is mediated by formation of nitric oxide (NO) and prostanoids, three different experimental models were studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1-10 μM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition of NO and prostanoid formation. Inhibition of these systems abolished the vasodilator effect of ATP. Cell-culture experiments verified ATP-induced formation of NO and prostacyclin in rat skeletal muscle microvascular endothelial cells, and ATP-induced formation of NO in rat skeletal muscle cells. To confirm these findings in humans, ATP was infused into skeletal muscle interstitium of healthy subjects via microdialysis probes and found to increase muscle interstitial concentrations of NO and prostacyclin by ~60% and ~40%, respectively. Collectively, these data suggest that a physiologically relevant elevation in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation.


Systemic tetracycline delays degradation of three different collagen membranes in rat calvaria.
The aim of this study was to quantitatively evaluate the effect of systemic tetracycline (TTC) on the degradation of three different collagen membranes. Collagen membranes were cut into 5 mm diameter membrane discs and labeled with aminohexanoyl-biotin-N-hydroxy-succinimide ester. One membrane disc each of a non-cross-linked [BioGide (BG)], glutaraldehyde cross-linked [BioMend Extend (BM)], and ribose cross-linked [Ossix (OS)] was implanted on the calvaria of 40 Wistar rats. Another 10 biotinylated collagen membrane discs from each membrane type were processed for histologic observation and served as baseline; half of them (five from each group) were also treated with formic acid to inspect possible interference with biotinilazation of collagen by formic acid used during the decalcification process. A 10 mg/kg dose of TTC (50% of the minimal recommended antibacterial dose) to the experimental (20 animals) and saline to the control (20 animals) group was administered intramuscularly every 3 days. From each group, block sections were retrieved in half of the animals after 14 days and in the remaining after 28 days. Decalcified tissue histology was stained with streptavidin horseradish peroxidase. A computer-assisted program measured the membranes' collagen contents. Statistical analysis consisted of analysis of variance (ANOVA) with repeated measures. No statistically significant differences in collagen contents were appreciated between biotinylated non-implanted membranes treated or not treated by formic acid. Systemic TTC had a different effect on the bio-degradation of the membranes: while it significantly decreased the resorption of two of the membranes (BG and BM), it had minimal influence on the ribose cross-linked membrane (OS). ANOVA with repeated measures, tests of within-subjects effects, showed a statistically significant difference between the membranes (P<0.001), within the membranes at the different time-points (P<0.001), a significant interaction between membranes and time and between the membranes and administered TTC (P<0.001). Test of between-subject effects revealed a statistically significant interaction with time and with TTC (P<0.001). Systemically administered TTC in sub-antibacterial doses may offer a possible treatment alternative to reduce bio-degradation and enhance bio-durability of certain collagen membranes. The findings of the present study could have clinical application in large non-self-contained bone defects, where prolonged membrane barrier functions are desirable.


Molecular dynamics simulation of structure, thermodynamic, and dynamic properties of poly(dimethylsilamethylene), poly(dimethylsilatrimethylene) and their alternating copolymer.
Molecular dynamics is used for the simulation of silicon-containing polymers with promising membrane material properties. An atomistic force field is developed for the description of bond bending, torsional angle variation, and nonbonded intra- and intermolecular interactions. Detailed ab initio quantum mechanics calculations on corresponding monomers that appeared recently in the literature are used for the parametrization of the bonded and nonbonded local intramolecular force field. For the intermolecular and nonbonded nonlocal intramolecular interactions, parameters are obtained from accurate force fields proposed in the literature for similar compounds. The force field is used subsequently for the calculation of thermodynamic, structure, and dynamic properties of two homopolymers, namely, poly(dimethylsilamethylene) and poly(dimethylsilatrimethylene), and their alternating copolymer. A wide range of temperatures and pressures is examined. Polymer systems of different molecular weights are simulated. Experimental data available for these polymers are very limited. In all cases, simulation results are in good agreement with these data. Furthermore, simulation results agree very well with empirical macroscopic correlations used widely for rubbery polymers for the properties under consideration.


Neurodevelopmental Outcomes in Infants Screened for Retinopathy of Prematurity.
Preterm infants screened for retinopathy of prematurity (ROP) are at risk for heterogenous neurodevelopment outcomes that are difficult to predict. To characterize the potential association between socioeconomic and clinical risk factors and neurodevelopmental outcomes in a diverse, multicenter cohort of premature neonates screened for ROP. This was a retrospective cohort study using electronic medical records and US Census Bureau income data. This study was performed at academic (University of California, Los Angeles [UCLA] Mattel Children's Hospital and UCLA Santa Monica Hospital), community (Cedars-Sinai Medical Center), and LA county (Harbor-UCLA Medical Center) neonatal intensive care units. Participants included infants who met American Academy of Pediatrics guidelines for ROP screening and had records from at least 1 Bayley Scales of Infant and Toddler Development (BSID) neurodevelopment assessment between 0 and 36 months of adjusted age. Data analyses were conducted from January 1, 2011, to September 1, 2022. Demographic and clinical information, proxy household income, and health insurance type were collected as risk factors. Neurodevelopmental outcomes in the cognitive, language, and motor domains measured via BSID were the primary outcomes. A total of 706 infants (mean [SD] age, 28.6 [2.4] weeks; 375 male [53.1%]) met inclusion criteria. In a multivariable model, which included adjustments for birth weight, sex, insurance type, intraventricular hemorrhage (IVH), and age at assessment, public health insurance was associated with a 4-fold increased risk of moderate to severe neurodevelopmental impairment (NDI) in cognitive and language domains (cognitive, odds ratio [OR], 3.65; 95% CI, 2.28-5.86; P = 8.1 × 10-8; language, OR, 3.96; 95% CI, 2.61-6.02; P = 1.0 × 10-10) and a 3-fold increased risk in the motor domain (motor, OR, 2.60; 95% CI, 1.59-4.24; P = 1.4 × 10-4). In this adjusted model, clinical factors that were associated with an increased risk of moderate to severe NDI included lower birth weight, diagnosis of IVH, male sex, and older age at time of Bayley assessment. In unadjusted analyses, infants who received either laser or anti-VEGF treatment, compared with infants without treatment-requiring ROP, had lower BSID scores in multiple domains at 0 to 12 months, 12 to 24 months, and 24 to 36 months (DATA). In the multivariable model, treatment type was no longer associated with worse neurodevelopmental outcomes in any domain. Study results suggest an association between public insurance type and NDI in a diverse population screened for ROP, indicating the complexities of neurodevelopment. This study also supports the early neurodevelopmental safety of anti-VEGF treatment, as anti-VEGF therapy was not found to be independently associated with worse NDI in any domain.


Obesity-exposed oocytes accumulate and transmit damaged mitochondria due to an inability to activate mitophagy.
Mitochondria are the most prominent organelle in the oocyte. Somatic cells maintain a healthy population of mitochondria by degrading damaged mitochondria via mitophagy, a specialized autophagy pathway. However, evidence from previous work investigating the more general macroautophagy pathway in oocytes suggests that mitophagy may not be active in the oocyte. This would leave the vast numbers of mitochondria - poised to be inherited by the offspring - vulnerable to damage. Here we test the hypothesis that inactive mitophagy in the oocyte underlies maternal transmission of dysfunctional mitochondria. To determine whether oocytes can complete mitophagy, we used either CCCP or AntimycinA to depolarize mitochondria and trigger mitophagy. After depolarization, we did not detect co-localization of mitochondria with autophagosomes and mitochondrial DNA copy number remained unchanged, indicating the non-functional mitochondrial population was not removed. To investigate the impact of an absence of mitophagy in oocytes with damaged mitochondria on offspring mitochondrial function, we utilized in vitro fertilization of high fat high sugar (HF/HS)-exposed oocytes, which have lower mitochondrial membrane potential and damaged mitochondria. Here, we demonstrate that blastocysts generated from HF/HS oocytes have decreased mitochondrial membrane potential, lower metabolites involved in ATP generation, and accumulation of PINK1, a mitophagy marker protein. This mitochondrial phenotype in the blastocyst mirrors the phenotype we show in HF/HS exposed oocytes. Taken together, these data suggest that the mechanisms governing oocyte mitophagy are fundamentally distinct from those governing somatic cell mitophagy and that the absence of mitophagy in the setting of HF/HS exposure contributes to the oocyte-to-blastocyst transmission of dysfunctional mitochondria.


Identification of a novel Cys2/His2-type zinc-finger protein as a component of a spermine-signaling pathway in tobacco.
In a previous work, we identified a Cys(2)/His(2)-type zinc-finger transcription repressor, (ZFT1), that functions in a spermine-mediated signal transduction pathway in tobacco plants. Database search disclosed the presence of another Cys(2)/His(2)-type zinc-finger protein ZFP1 (accession number AAC06243) in tobacco plants. In this work, we characterized ZFP1 and investigated whether this protein is also involved in a Spm-signaling pathway. This factor showed the highest identity to petunia ZPT2-2 and higher similarity to petunia ZPT2-3, Arabidopsis STZ/ZAT10, soybean SCOF-1, red pepper CAZFP1/CaPIF1 as well as to tobacco ZFT1. ZFP1 localized to the nucleus and had a specific DNA-binding activity, supportive to be a transcription factor. Furthermore, the protein had a mild repression activity on transcription in plant cells. The expression of ZFP1, encoding ZFP1, was upregulated during tobacco mosaic virus-induced hypersensitive response. ZFP1 expression was also induced by exogenously applied spermine and its induction was repressed by inhibitors of amine oxidase/polyamine oxidase. Collectively, our data indicate that ZFP1 is a new transcription factor which functions in a spermine-signaling pathway in tobacco.


Phylogenetic analysis of nuclear and mitochondrial genes reveals evolutionary relationships and mitochondrial introgression in the sertifer species group of the genus Neodiprion (Hymenoptera: Diprionidae).
Neodiprion Rohwer (Hymenoptera: Diprionidae) is a Holarctic genus of conifer-feeding sawflies with a remarkable amount of inter- and intraspecific diversity in host use, behavior, and development. This variation is thought to play a central role in Neodiprion diversification, but speciation hypotheses remain untested due to a lack of a robust phylogenetic estimate. Here, we utilize sequence data from three nuclear genes (CAD, ANL43, EF1alpha) to obtain a phylogenetic estimate for the genus. These analyses suggest that: (1) North American and Eurasian Neodiprion are monophyletic sister clades, (2) the sertifer group is paraphyletic with respect to the monophyletic lecontei group, and (3) on at least two occasions, dispersal from eastern to western North America proceeded via southern host bridges. Based on these results and host biogeography, we revise a previous scenario for the evolution of Neodiprion and suggest maximum ages for the genus and for the lecontei group (25 My and 14 My, respectively). In addition, because a previous study reported rampant mitochondrial introgression in the lecontei group, we assess its prevalence in the sertifer group. Analysis of three mitochondrial genes (COI, tRNA-leucine, and COII) reveals that mito-nuclear discordance is prevalent in the sertifer group, and patterns of species monophyly are consistent with those expected under frequent mitochondrial introgression. As was the case for lecontei group species, we find that introgression appears to be most pronounced between species that occasionally share hosts, suggesting that divergent host use is an important barrier to gene flow in Neodiprion. Finally, we suggest that the lack of phylogenetic resolution and prevalence of species non-monophyly in the non-Pinus feeding Neodiprion may result from the rapid divergence (possibly with gene flow) of these species following their entry into a novel adaptive zone.


Gene expression of bone matrix proteins and endothelin receptors in endothelin-1-deficient mice revealed by in situ hybridization.
Endothelin-1 (ET-1) was first found as a vasoconstrictor protein excreted by vascular endothelial cells, but recently ET-1 has been considered to have widespread functions that include regulation of osteochondrogenic metabolism. We analyzed sections of head regions in ET-1 knockout mice that are known to have abnormalities in pharyngeal arch-derived tissues and found that there was severe hypoplasia in facial bones. The hypoplasia suggests that the matrix mineralization system of facial bones is disrupted in ET-1-/- homozygous mice. To elucidate whether osteogenic cells in facial bones are the targets for ET-1 and whether expression of bone matrix genes are modulated by ET-1, we examined gene expression of ET-1 receptors, ETA and ETB, and that of the bone matrix proteins, osteonectin (ON) and osteopontin (OP), both in the head regions of ET-1+/- heterozygous and ET-1-/- homozygous mice by means of in situ hybridization. Different patterns of expression between ETA and ETB mRNAs were observed in both groups. In 18.5 days post coitus fetuses, ETA mRNA was most strongly expressed in osteogenic cells along craniofacial bones, but ETB mRNA was most strongly expressed in trunks of trigeminal nerve. This finding suggests that ET-1 may modulate osteogenic cells through ETA receptor but not through ETB receptor. The expression patterns of ETA, OP, and ON mRNAs were distinct between the two groups. In the lower jaw of ET-1+/- heterozygous mice, the ETA, ON, and OP mRNA positive cells were scattered in the inner and outer regions of the thick bone matrix, but in ET-1-/- homozygous mice, cells containing those mRNAs were located close to each other at the surface of thin bone matrix. However, cellular expression of ON and OP mRNAs in osteogenic cells of ET-1-/- homozygous mice was not suppressed as compared with ET-1+/- heterozygous mice. We conclude that ET-1 may regulate proliferation and migration of osteogenic cells in the maxillofacial region, rather than modulating the expression level of ON and OP mRNAs.


The tomato I-3 gene: a novel gene for resistance to Fusarium wilt disease.
Plant resistance proteins provide race-specific immunity through the recognition of pathogen effectors. The resistance genes I, I-2 and I-3 have been incorporated into cultivated tomato (Solanum lycopersicum) from wild tomato species to confer resistance against Fusarium oxysporum f. sp. lycopersici (Fol) races 1, 2 and 3, respectively. Although the Fol effectors corresponding to these resistance genes have all been identified, only the I-2 resistance gene has been isolated from tomato. To isolate the I-3 resistance gene, we employed a map-based cloning approach and used transgenic complementation to test candidate genes for resistance to Fol race 3. Here, we describe the fine mapping and sequencing of genes at the I-3 locus, which revealed a family of S-receptor-like kinase (SRLK) genes. Transgenic tomato lines were generated with three of these SRLK genes and one was found to confer Avr3-dependent resistance to Fol race 3, confirming it to be I-3. The finding that I-3 encodes an SRLK reveals a new pathway for Fol resistance and a new class of resistance genes, of which Pi-d2 from rice is also a member. The identification of I-3 also allows the investigation of the complex effector-resistance protein interaction involving Avr1-mediated suppression of I-2- and I-3-dependent resistance in tomato.


Vascular proliferation is increased in basal-like breast cancer.
Based on molecular sub-classification, basal-like breast cancer is associated with aggressive behavior. These tumors are frequently triple negative and lack traditional treatment targets. Angiogenesis, one of the hallmarks of cancer, is important for the local growth and spread of malignant tumors and is now a treatment target. The aim of this study was to explore whether angiogenesis is increased in relation to certain molecular subtypes of breast cancer with special focus on the basal-like category. Altogether, we analyzed a total of 431 breast cancers from two independent series after dual immunohistochemical staining of Factor VIII for endothelial cells and Ki-67 for proliferating cells. We then determined vascular proliferation in the most vascularized areas of the tumor. In both Series I and II, high vascular proliferation index (VPI) was significantly associated with expression of cytokeratin 5/6 (P = 0.001, 0.010), P-cadherin (P < 0.0005, <0.0005), epidermal growth factor receptor (P = 0.003, 0.001), the basal-like subtype (P = 0.001, 0.011), and the core basal phenotype (P = 0.002, 0.002), respectively. In Series I, high VPI was associated with the triple negative phenotype (P = 0.004) and p63 expression (P = 0.008). Tumor angiogenesis, as measured by vascular proliferation, was increased in the basal-like subtype in two independent breast cancer series and may thus be a possible treatment target in this category. Studies are required to evaluate whether this novel angiogenesis marker can be used to stratify patients for anti-angiogenesis treatment.


The UBX domain: a widespread ubiquitin-like module.
The UBX domain is an 80 amino acid residue module that is present typically at the carboxyl terminus of a variety of eukaryotic proteins. In an effort to elucidate the function of UBX domains, we solved the three-dimensional structure of the UBX domain of human Fas-associated factor-1 (FAF1) by NMR spectroscopy. The structure has a beta-Grasp fold characterised by a beta-beta-alpha-beta-beta-alpha-beta secondary-structure organisation. The five beta strands are arranged into a mixed sheet in the order 21534. The longer first helix packs across the first three strands of the sheet, and a second shorter 3(10) helix is located in an extended loop connecting strands 4 and 5. In the absence of significant sequence similarity, the UBX domain can be superimposed with ubiquitin with an r.m.s.d. of 1.9 A, suggesting that the two structures share the same superfold, and an evolutionary relationship. However, the absence of a carboxyl-terminal extension containing a double glycine motif and of suitably positioned lysine side-chains makes it highly unlikely that UBX domains are either conjugated to other proteins or part of mixed UBX-ubiquitin chains. Database searches revealed that most UBX domain-containing proteins belong to one of four evolutionarily conserved families represented by the human FAF1, p47, Y33K, and Rep8 proteins. A role of the UBX domain in ubiquitin-related processes is suggested.


Fast Intracortical Sensory-Motor Integration: A Window Into the Pathophysiology of Parkinson's Disease.
Parkinson's Disease (PD) is a prototypical basal ganglia disorder. Nigrostriatal dopaminergic denervation leads to progressive dysfunction of the cortico-basal ganglia-thalamo-cortical sensorimotor loops, causing the classical motor symptoms. Although the basal ganglia do not receive direct sensory input, they are important for sensorimotor integration. Therefore, the basal ganglia dysfunction in PD may profoundly affect sensory-motor interaction in the cortex. Cortical sensorimotor integration can be probed with transcranial magnetic stimulation (TMS) using a well-established conditioning-test paradigm, called short-latency afferent inhibition (SAI). SAI probes the fast-inhibitory effect of a conditioning peripheral electrical stimulus on the motor response evoked by a TMS test pulse given to the contralateral primary motor cortex (M1). Since SAI occurs at latencies that match the peaks of early cortical somatosensory potentials, the cortical circuitry generating SAI may play an important role in rapid online adjustments of cortical motor output to changes in somatosensory inputs. Here we review the existing studies that have used SAI to examine how PD affects fast cortical sensory-motor integration. Studies of SAI in PD have yielded variable results, showing reduced, normal or even enhanced levels of SAI. This variability may be attributed to the fact that the strength of SAI is influenced by several factors, such as differences in dopaminergic treatment or the clinical phenotype of PD. Inter-individual differences in the expression of SAI has been shown to scale with individual motor impairment as revealed by UPDRS motor score and thus, may reflect the magnitude of dopaminergic neurodegeneration. The magnitude of SAI has also been linked to cognitive dysfunction, and it has been suggested that SAI also reflects cholinergic denervation at the cortical level. Together, the results indicate that SAI is a useful marker of disease-related alterations in fast cortical sensory-motor integration driven by subcortical changes in the dopaminergic and cholinergic system. Since a multitude of neurobiological factors contribute to the magnitude of inhibition, any mechanistic interpretation of SAI changes in PD needs to consider the group characteristics in terms of phenotypical spectrum, disease stage, and medication.


LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study.
The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Adult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70. Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported. LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.


Neuregulins at the neuromuscular synapse: past, present, and future.
At the developing vertebrate neuromuscular junction, neuregulins are growth/differentiation factors essential for terminal Schwann cell survival. Neuregulins have also been thought as the critical signals responsible for the increased transcription of acetylcholine receptor subunit genes at the neuromuscular synapse. This latter role is now highly controversial. This article reviews the evidence that has shaped the views of the neuregulins and how these views have been challenged. The most recent experiments indicate that neuregulin signaling to postsynaptic muscle fibers may modulate, rather than determine, acetylcholine receptor expression at the neuromuscular junction. Based on findings from my lab and those of others, I propose that this modulation might involve novel posttranscriptional molecular mechanisms. Finally, I also suggest that neuregulin signaling may have an important role to play in mediating the response of adult terminal Schwann cells to denervation.


External validation of the "walking estimated limitation calculated by history" (WELCH) questionnaire in patients with claudication.
To externally validate the recently proposed "Walking Estimated Limitation Calculated by History" (WELCH) questionnaire. A prospective study was performed on 450 new patients referred to our laboratory for treadmill testing (constant load 3.2 km/h and 10% slope for 15 minutes and then incremental increases). Results are presented as mean ± SD or median [25th-75th percentiles] or number (percentage). An ankle brachial index <0.90 defined the presence of peripheral artery disease (PAD). Typical "vascular-type claudication" is a lower-limb pain or discomfort that is absent at rest, appears at exercise, forces stopping, and disappears within 10 minutes of exercise stopping. The Spearman r coefficient of correlation between maximal walking time (MWT) on treadmill and WELCH scores was calculated for patients with (PAD+) or without (PAD-) PAD, and reporting typical vascular-type claudication (VTC+) or not (VTC-). The WELCH score was obtained in all included patients. The number (%) of patients with a WELCH score <25 was 37 (54%), 198 (65%), 14 (44%), and 18 (38%), and the Spearman correlation coefficient between WELCH score and treadmill MWT was 0.588, 0.609, 0.581, and 0.591 in the VTC-/PAD+, VTC+/PAD+, VTC-/PAD-, and VTC+/PAD- groups respectively (all p < .001). In PAD+/VTC+ patients, the WELCH positive predictive value for the inability to walk for 5 minutes on the treadmill was 79%. The WELCH score correlates moderately with treadmill-walking capacity in patients with or without PAD, and with or without typical VTC. It appears to be a simple to complete and easily scored instrument to help clinicians standardise the subjective estimation of walking capacity in their patients.


Selection by pollinators on floral traits in generalized Trollius ranunculoides (Ranunculaceae) along altitudinal gradients.
Abundance and visitation of pollinator assemblages tend to decrease with altitude, leading to an increase in pollen limitation. Thus increased competition for pollinators may generate stronger selection on attractive traits of flowers at high elevations and cause floral adaptive evolution. Few studies have related geographically variable selection from pollinators and intraspecific floral differentiation. We investigated the variation of Trollius ranunculoides flowers and its pollinators along an altitudinal gradient on the eastern Qinghai-Tibet Plateau, and measured phenotypic selection by pollinators on floral traits across populations. The results showed significant decline of visitation rate of bees along altitudinal gradients, while flies was unchanged. When fitness is estimated by the visitation rate rather than the seed number per plant, phenotypic selection on the sepal length and width shows a significant correlation between the selection strength and the altitude, with stronger selection at higher altitudes. However, significant decreases in the sepal length and width of T. ranunculoides along the altitudinal gradient did not correspond to stronger selection of pollinators. In contrast to the pollinator visitation, mean annual precipitation negatively affected the sepal length and width, and contributed more to geographical variation in measured floral traits than the visitation rate of pollinators. Therefore, the sepal size may have been influenced by conflicting selection pressures from biotic and abiotic selective agents. This study supports the hypothesis that lower pollinator availability at high altitude can intensify selection on flower attractive traits, but abiotic selection is preventing a response to selection from pollinators.


Examining Different Motor Learning Paradigms for Improving Balance Recovery Abilities Among Older Adults, Random vs. Block Training-Study Protocol of a Randomized Non-inferiority Controlled Trial.
Introduction: Falls are the leading cause of fatal and nonfatal injuries among older adults. Studies showed that older adults can reduce the risk of falls after participation in an unexpected perturbation-based balance training (PBBT), a relatively novel approach that challenged reactive balance control. This study aims to investigate the effect of the practice schedule (i.e., contextual interference) on reactive balance function and its transfer to proactive balance function (i.e., voluntary step execution test and Berg balance test). Our primary hypothesis is that improvements in reactive balance control following block PBBT will be not inferior to the improvements following random PBBT. Methods and Analysis: This is a double-blind randomized controlled trial. Fifty community-dwelling older adults (over 70 years) will be recruited and randomly allocated to a random PBBT group (n = 25) or a block PBBT group (n = 25). The random PBBT group will receive eight training sessions over 4 weeks that include unexpected machine-induced perturbations of balance during hands-free treadmill walking. The block PBBT group will be trained by the same perturbation treadmill system, but only one direction will be trained in each training session, and the direction of the external perturbations will be announced. Both PBBT groups (random PBBT and block PBBT) will receive a similar perturbation intensity during training (which will be customized to participant's abilities), the same training period, and the same concurrent cognitive tasks during training. The generalization and transfer of learning effects will be measured by assessing the reactive and proactive balance control during standing and walking before and after 1 month of PBBT, for example, step and multiple steps and fall thresholds, Berg balance test, and fear of falls. The dependent variable will be rank transformed prior to conducting the analysis of covariance (ANCOVA) to allow for nonparametric analysis. Discussion: This research will explore which of the balance retraining paradigms is more effective to improve reactive balance and proactive balance control in older adults (random PBBT vs. block PBBT) over 1 month. The research will address key issues concerning balance retraining: older adults' neuromotor capacities to optimize training responses and their applicability to real-life challenges. Clinical Trial Registration: Helsinki research ethics approval has been received (Soroka Medical Center approval #0396-16-SOR; MOH_2018-07-22_003536; www.ClinicalTrials.gov, NCT04455607).


Postoperative pain care.
In addition to decreasing patient suffering, adequate perioperative pain control is necessary for healing and recovery. Perioperative pain care is a proactive plan based on assessments and individualized interventions to inhibit nociception while controlling other symptoms and applying analgesic principles to promote rehabilitation with continuous evaluation.


Analysing the impact of body position shift on sleep architecture and stage transition: A comprehensive multidimensional study using event-synchronised polysomnography data.
Although understanding the physiological mechanisms of obstructive sleep apnea (OSA) is important for treating OSA, limited studies have examined OSA patients' sleep architecture at the epoch-by-epoch level and analysed the impact of sleep position and stage on OSA pathogenesis. The epoch-labelled polysomnogram was analysed multidimensionally to investigate the effect of sleep position on the sleep architecture and risk factors of apnea in patients with OSA. This retrospective multicentric case-control study reviewed full-night diagnostic polysomnography of 6983 participants. The difference in the proportion of time spent supine during non-rapid eye movement (NREM) and REM stages, and the mean duration of respiratory events per body position were evaluated. The frequency of sleep stage transition per body position shift type was computed. Further subgroup analysis was performed based on OSA severity and positional dependency. Supine time in patients with OSA varied across sleep stages, with lower proportions in N3 and REM, and shorter durations with severity. Patients with OSA spent less time in supine positions during N3 and REM, and experienced longer apnea events in both positions compared to the control group. The frequency of all sleep stage transitions increased with OSA severity and was higher among non-positional OSA than positional OSA and the control group, regardless of body position shift type. The sleep stage transition from N3 and REM to wakefulness was notably heightened during position shift. Understanding the sleep architecture of patients with OSA requires analysing various sleep characteristics including sleep position simultaneously, with future studies focusing on position detection to predict sleep stages and respiratory events.


Anti-inflammatory activity of β-glucans from different sources before and after fermentation by fecal bacteria in vitro.
β-Glucans are widely sourced and have various physiological effects, including anti-inflammatory effects. However, the strength of the anti-inflammatory activity of β-glucans from different sources remains unknown due to the lack of rapid and effective biomarkers. This study therefore aimed to screen out the β-glucans with strong anti-inflammatory activity from five different sources and to further screen out possible biomarkers in metabolites after fermenting the β-glucans with gut microorganisms. The results showed that all five β-glucans inhibited the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators and suppressed the mRNA expression level of TLR4/MyD88. Their anti-inflammatory mechanisms involved the inhibition of intracellular reactive oxygen species (ROS) production and suppression of mRNA expression of the NF-κB pathway and JNK pathway. Among them, barley β-glucan exhibited the strongest anti-inflammatory effect, followed by Ganoderma lucidum β-glucan. Enhanced anti-inflammatory activity of β-glucan was found after fermentation and may be related to the increased abundance of metabolites such as vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid. They were strongly positively correlated to the abundance of beneficial bacteria such as Blautia, suggesting that the production of those metabolites may be responsible for the flourishing of the beneficial bacteria. In conclusion, barley was a preferred raw material for the preparation of β-glucans with strong anti-inflammatory activity. Vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid were the possible biomarkers that could be utilized to evaluate the anti-inflammatory effect of β-glucans. © 2023 Society of Chemical Industry.


Remodeling of the Rad51 DNA strand-exchange protein by the Srs2 helicase.
Homologous recombination is associated with the dynamic assembly and disassembly of DNA-protein complexes. Assembly of a nucleoprotein filament comprising ssDNA and the RecA homolog, Rad51, is a key step required for homology search during recombination. The budding yeast Srs2 DNA translocase is known to dismantle Rad51 filament in vitro. However, there is limited evidence to support the dismantling activity of Srs2 in vivo. Here, we show that Srs2 indeed disrupts Rad51-containing complexes from chromosomes during meiosis. Overexpression of Srs2 during the meiotic prophase impairs meiotic recombination and removes Rad51 from meiotic chromosomes. This dismantling activity is specific for Rad51, as Srs2 Overexpression does not remove Dmc1 (a meiosis-specific Rad51 homolog), Rad52 (a Rad51 mediator), or replication protein A (RPA; a single-stranded DNA-binding protein). Rather, RPA replaces Rad51 under these conditions. A mutant Srs2 lacking helicase activity cannot remove Rad51 from meiotic chromosomes. Interestingly, the Rad51-binding domain of Srs2, which is critical for Rad51-dismantling activity in vitro, is not essential for this activity in vivo. Our results suggest that a precise level of Srs2, in the form of the Srs2 translocase, is required to appropriately regulate the Rad51 nucleoprotein filament dynamics during meiosis.


Experimentally quantifying the feasible torque space of the human shoulder.
Daily tasks rely on our ability to generate multi-dimensional shoulder torques. When function is limited, strength assessments are used to identify impairments and guide treatment. However, these assessments are often one-dimensional and limited in their sensitivity to diagnose shoulder pathology. To address these limitations, we have proposed novel metrics to quantify shoulder torque capacity in all directions. To quantify the feasible torque space of the shoulder, we measured maximal volitional shoulder torques in 32 unique directions and fit an ellipsoid model to these data. This ellipsoid model was used to quantify overall strength magnitude, strength balance, and the directions in which participants were strongest and weakest. We used these metrics to characterize three-dimensional shoulder strength in healthy adults and demonstrated their repeatability across days. Finally, using musculoskeletal simulations, we showed that our proposed metrics can distinguish between changes in muscle strength associated with aging or rotator cuff tears and quantified the influence of altered experimental conditions on this diagnostic capacity. Our results demonstrate that the proposed metrics can robustly quantify the feasible torque space of the shoulder and may provide a clinically useful description of the functional capacity of the shoulder in health and disease.


[Microflora of active ooze participating in the decomposition of sulfanilic acid].
Microflora of domestic water can be a source of active ooze adapted to sulphanilic acid. Adaptation of the microflora to sulphanilic acid at a concentration of 170-200 mg/l takes 6 to 8 days. The microflora of active ooze, immediately after adaptation, consists mainly of Pseudomonas species, Ps. denitrificans, Ps. fluorescens, Ps. striata, Ps. putida, etc., and also of Achromobacter stutzeri, Achromobacter flavum, Mycobacterium phlei, Mycobacterium mucosum, Bacillus mesentericus, Bac. cereus, saccharomyces cerevisiae, Schizosaccharomyces pombe, and Rhodotorula glutinus. The number of the species decreased as a result of long cultivation of active ooze on a minimal medium with sulphanilic acid as a sole source of carbon and nitrogen; the following strains prevailed: Ps. putida, Ps. eisenbergii, strains of Mycobacterium phlei and Flavobacterium solare. The isolated strains of Ps. putida and Ps. eisenbergii decomposed sulphanilic acid by 60.0--79.5 percent, and together with Mycobacterium phlei by 100 percent during 4 to 7 days. The ability to oxidize sulphanilic acid decreased after storage. Addition to the medium of other sources of carbon, nitrogen and vitamins did not restore the lost ability of the microorganisms to decompose sulphanilic acid.


"We Are Young, We Run Free": Predicting Factors of Life Satisfaction among Young Backpackers.
Although research from a positive psychology perspective is conducted among different populations, few studies have examined the predictors of life satisfaction among young backpackers. The current study focused on young adults (ages 21-30), an age group for whom backpacking treks are a growing phenomenon, during their treks in the Far East and South America. Direct and indirect models were used to identify personal factors and environmental resources contributing to life satisfaction. After at least one month abroad, 318 young adults (M = 23.76) answered a self-report quantitative questionnaire. The findings show that personal resources, social support, and community participation were positively associated with life satisfaction, and risk-taking behaviors were negatively associated with life satisfaction. Social support and community participation partially mediated the association between risk-taking behaviors and life satisfaction and between personal resources and life satisfaction. The implications of the findings for the subjective well-being of young backpackers during their transition to adulthood include, among others, the need to help young backpackers maintain their personal and social resources as valuable assets for coping with challenges during their trips. It is also important to increase awareness of the possible wide-ranging negative effects of risk-taking behaviors during backpacking trips.


Chemical, thermal, and electric field induced unfolding of single protein molecules studied using nanopores.
Single-molecule experimental techniques have recently shown to be of significant interest for use in numerous applications in both the research laboratory and industrial settings. Although many single-molecule techniques exist, the nanopore platform is perhaps one of the more popular techniques due to its ability to act as a molecular sensor of biological macromolecules. For example, nanopores offer a unique, new method for probing various properties of proteins and can contribute to elucidating key biophysical information in conjunction with existing techniques. In the present study, various forms of bovine serum albumin (BSA) are detected including thermally refolded BSA, urea-denatured BSA, and multiple forms of BSA detected at elevated electric field strengths (with and without urea). We also provide excluded volume measurements for each of these states that normally are difficult to obtain due to unknown and unstable protein conformations.


Massive ascites in systemic lupus erythematosus.
We report a 59-year-old woman who developed massive, painless ascites attributed to systemic lupus erythematosus. Extensive investigations, including exploratory laparotomy, failed to demonstrate hepatic, renal, cardiac, infectious, or malignant disease. Therapy with systemic corticosteroids resulted in dramatic disappearance of ascites which has not recurred after 2 years.


Bone marrow transplants in chronic myelogenous leukemia: an overview of determinants of survival.
The success of bone marrow transplantation in chronic myelogenous leukemia (CML) is strongly associated with the phase of the disease at the time of transplantation. For allogeneic transplants from siblings with identical human leukocyte antigens, the 3-year survival rate for recipients in chronic phase ranges from 55% to 70%, whereas survival falls to approximately 30% for recipients in accelerated phase and to 0% to 20% for patients receiving transplants during blast crisis. Detailed analysis of data pooled from 405 patients demonstrated that the 3-year probability of relapse was 48% for recipients of T-cell-depleted bone marrow, but only 9% for recipients of non-T-cell-depleted bone marrow (relative risk, 5.4; P less than .0001). Regardless of transplant T-cell status, however, patients who developed chronic graft-versus-host disease (GVHD) were less likely to relapse at 4 years when compared with recipients without chronic GVHD (6% v 24%; relative risk, 3.1; P less than .01). Survival was correlated with severity of acute GVHD and age. Allogeneic bone marrow transplantation from unrelated donors can be useful in expanding the patient population eligible for transplantation. A study of recipients of transplants from unrelated donors showed a 3-year projected survival of 55% for chronic phase patients, and 22% for patients with advanced disease. However, a high rate of graft failure (10%) and grade II to IV acute GVHD can be expected. Preliminary data suggest that ex vivo treatment of autologous bone marrow with interferon can effect complete or partial Philadelphia (Ph) chromosome negative bone marrow mosaicism, although appearance of Ph chromosome negative metaphases may not be persistent. Thus, interferon treatment of autologous bone marrow may play a more significant role in the treatment of CML.


Reconstruction and Simulation of a Scaffold Model of the Cerebellar Network.
Reconstructing neuronal microcircuits through computational models is fundamental to simulate local neuronal dynamics. Here a scaffold model of the cerebellum has been developed in order to flexibly place neurons in space, connect them synaptically, and endow neurons and synapses with biologically-grounded mechanisms. The scaffold model can keep neuronal morphology separated from network connectivity, which can in turn be obtained from convergence/divergence ratios and axonal/dendritic field 3D geometries. We first tested the scaffold on the cerebellar microcircuit, which presents a challenging 3D organization, at the same time providing appropriate datasets to validate emerging network behaviors. The scaffold was designed to integrate the cerebellar cortex with deep cerebellar nuclei (DCN), including different neuronal types: Golgi cells, granule cells, Purkinje cells, stellate cells, basket cells, and DCN principal cells. Mossy fiber inputs were conveyed through the glomeruli. An anisotropic volume (0.077 mm3) of mouse cerebellum was reconstructed, in which point-neuron models were tuned toward the specific discharge properties of neurons and were connected by exponentially decaying excitatory and inhibitory synapses. Simulations using both pyNEST and pyNEURON showed the emergence of organized spatio-temporal patterns of neuronal activity similar to those revealed experimentally in response to background noise and burst stimulation of mossy fiber bundles. Different configurations of granular and molecular layer connectivity consistently modified neuronal activation patterns, revealing the importance of structural constraints for cerebellar network functioning. The scaffold provided thus an effective workflow accounting for the complex architecture of the cerebellar network. In principle, the scaffold can incorporate cellular mechanisms at multiple levels of detail and be tuned to test different structural and functional hypotheses. A future implementation using detailed 3D multi-compartment neuron models and dynamic synapses will be needed to investigate the impact of single neuron properties on network computation.


Trends in hysterectomy for genital prolapse: rural experience.
The present study was conducted to investigate the trends of vaginal hysterectomy for genital prolapse in last 20 years by analyzing case records of affected women. During the analysis period, 4831 women underwent hysterectomy; records of 4223 (87.5%) were available. Of these, 911 (21.6%), 2.7% of 34,080 gynecological admissions, had vaginal hysterectomy for genital prolapse (study subjects). Eighty percent women who had vaginal hysterectomy for genital prolapse were over 40 years of age; however, most of these women had had the disorder for years before they presented. Only 4 (0.4%) women had not given birth, 874 (96%) women had had two or more births, and 383 (42%) had had 5 or more births. Having given birth was the major factor responsible for genital prolapse. In all, 94.2% of women presented with something coming out of the vagina." Some women presented with abnormal vaginal bleeding or pain in abdomen as the chief complaint although they had had uterovaginal prolapse for years. There was no mortality and morbidity decreased over the years. There has been no change in the rate of vaginal hysterectomy for genital prolapse over the years. Surgical morbidity decreased trend, possibly because of the preoperative, intraoperative, and postoperative precautions taken, especially preoperative treatment of urinary and genital tract infection. Attempts need to be made to have safe births and a healthy life style so as to prevent genital prolapse and in case it occurs, therapy to prevent progression so that major interventions like hysterectomy are averted. Meticulous preoperative evaluation and planned therapy help in reducing surgical morbidity, if surgery becomes essential.


The history of urology in Cleveland, Ohio.
Urology in Cleveland, as in the rest of the country, has evolved greatly over the past century. The recent passing of Resnick and Novick warrants a review of Cleveland's rich urological history. We reviewed historical and scientific literature and interviewed Cleveland urologists. Lower joined his cousin Crile as professor at Case Western Reserve University (CWRU) before they cofounded the Cleveland Clinic (CC) in 1921. Goldblatt at CWRU discovered renovascular hypertension, leading Poutasse at CC to develop renovascular arteriography and bypass surgery. Kolff brought his greatest invention, dialysis, to the United States when he joined CC. Straffon put CC's renal transplant program on the map through his success with deceased donor transplants. Persky, renowned at radical prostatectomies, chaired urology at CWRU for nearly 30 years and trained 6 future university department chairpersons. Resnick succeeded him and became one of the eminent figures in urology; an authority on numerous subjects, president of the American Urological Association and American Board of Urology (ABU) and Editor of the Journal of Urology. Novick, who became chairman at CC in 1985, was the consummate renal surgeon; he was adept at renal revascularization and transplantation, but his greatest surgical innovation was the partial nephrectomy. He likewise held many positions, including president of the ABU. Cleveland has been a driving force in the evolution of urology in the last century. Resnick and Novick led a golden age of urology for several decades until their recent untimely passings.


Wavelength-dependent change of retinal nerve fiber layer reflectance in glaucomatous retinas.
Retinal nerve fiber layer (RNFL) reflectance is often used in optical methods for RNFL assessment in clinical diagnosis of glaucoma, yet little is known about the reflectance property of the RNFL under the development of glaucoma. This study measured the changes in RNFL reflectance spectra that occurred in retinal nerve fiber bundles with different degrees of glaucomatous damage. A rat model of glaucoma with laser photocoagulation of trabecular meshwork was used. Reflectance of the RNFL in an isolated retina was measured at wavelengths of 400-830 nm. Cytostructural distribution of the bundles measured optically was evaluated by confocal imaging of immunohistochemistry staining of cytoskeletal components, F-actin, microtubules, and neurofilaments. RNFL reflectance spectra were studied in bundles with normal-looking appearance, early F-actin distortion, and apparent damage of all cytoskeletal components. Changes of RNFL reflectance spectra were studied at different radii (0.22, 0.33, and 0.44 mm) from the optic nerve head (ONH). Bundles in 30 control retinas and 41 glaucomatous retinas were examined. In normal retinas, reflectance spectra were similar along the same bundles. In glaucomatous retinas, reflectance spectra changed along bundles with the spectra becoming flatter as bundle areas approached the ONH. Elevation of intraocular pressure (IOP) causes nonuniform changes in RNFL reflectance across wavelengths. Changes of reflectance spectra occur early in bundles near the ONH and prior to apparent cytoskeletal distortion. Using the ratio of RNFL reflectance measured at different wavelengths can provide early and sensitive detection of glaucomatous damage.


Characterization of crystalline L-carnosine Zn(II) complex (Z-103), a novel anti-gastric ulcer agent: tautomeric change of imidazole moiety upon complexation.
A novel crystalline Zn(II) complex of L-carnosine was prepared and evaluated for inhibitory activity against gastric ulceration in rats. The complex was found to be much more active than various other Zn(II) compounds. It was characterized by means of infrared (IR) spectroscopy, solid-state carbon-13 (13C) and nitrogen-15 (15N) 1H-cross-polarization (CP) magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The spectroscopic data indicated that L-carnosine coordinates to Zn(II) as a quadridentate ligand. A comparison of the 13C-NMR signals of the imidazole carbons of the complex with those of several histidine derivatives revealed that a tautomeric change of imidazole moiety had occurred upon complexation. The binding mode of the complex was considered to be analogous to that of the corresponding Cu(II) complex.


Discovery of Akt kinase inhibitors through structure-based virtual screening and their evaluation as potential anticancer agents.
Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC50 values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC50 for HEK-293/IC50 for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.


Effects of a 6-Week Neuromuscular Rehabilitation Program on Ankle-Evertor Strength and Postural Stability in Elite Women Field Hockey Players With Chronic Ankle Instability.
To determine whether a neuromuscular rehabilitation program can improve postural stability and ankle-evertor strength and to examine the temporal changes and persistence of the rehabilitation effects in athletes with chronic ankle instability (CAI). A total of 21 national women field hockey players participated in this study (CAI, n = 12; control, n = 9). Isokinetic ankle-evertor strength (peak torque [PT], total work [TW]) at 30°/s, 60°/s, 90°/s, and 120°/s, mediolateral stability index (MSI), and dynamic stability test (TCT). Data were recorded at baseline, 6 wk, and 24 wk. At baseline, isokinetic evertor strength was comparable between groups. At 6 wk, the CAI group demonstrated significantly increased eccentric PT and TW at 30°/s and 60°/s and increased concentric/eccentric TW at 90°/s. The control group showed significantly increased concentric TW at 30°/s and increased concentric PT and TW at 90°/s. At 24 wk, except for eccentric PT at 60°/s and 120°/s, concentric/eccentric PT and TW were significantly increased in the CAI group. The control group showed significantly increased TW at all angular velocities regardless of contraction mode. The CAI group exhibited significant increases in concentric/eccentric evertor PT and TW at 120°/s in comparison with the control group. MSI and TCT decreased in both groups at 6 wk; however, the CAI group demonstrated significant increases in both measures at 24 wk, whereas the control group showed no significant change. The results suggest that the neuromuscular rehabilitation program had an immediate effect on gaining eccentric evertor strength and improving postural control and appeared to contribute to enhancing the evertor strength of unstable ankles in the longer term. On the other hand, improved postural stability did not seem to persist.


Prevalence of and Factors Associated With High Blood Pressure at 15 Years of Age: A Birth Cohort Study.
Arterial hypertension is the greatest cause of morbidity and mortality worldwide. Our aim was to investigate the prevalence of and factors associated with high blood pressure (HBP) among adolescents. The Pelotas 2004 Birth Cohort included 4231 newborns from hospital births in Pelotas, Brazil. A digital automatic OMRON sphygmomanometer (model HEM 742) was used to measure blood pressure on 3 occasions (at 6, 11, and 15 years of age). Those with blood pressure ≥95th percentile for age, height, and sex on each of the 3 occasions were considered as presenting HBP. Independent variables included family (income and history of arterial hypertension), maternal (schooling, age, pregestational body mass index, and smoking during pregnancy), and adolescent characteristics at birth (sex, skin color, gestational age, intrauterine growth, and systolic and diastolic genetic factors), and at 15 years (sleep, physical activity, sodium intake, screen time, work, body mass index, fat mass index, fat-free mass index, growth pattern, and puberty status). The prevalence of HBP (95% CI) was calculated. Crude and adjusted odds ratios (ORs) stratified by sex were obtained by logistic regression. A total of 1417 adolescents with complete information on blood pressure on the 3 occasions were analyzed. The prevalence of HBP was 3.2% (95% CI, 1.9%-4.5%) in female adolescents and 4.3% (95% CI, 2.8%-5.8%) in male adolescents. Female adolescents with a family history of arterial hypertension had a 3 times higher chance of HBP than their counterparts (OR, 3.1 [95% CI, 1.26-7.54]). In male adolescents, excessive maternal pregestational weight was associated with a 2.3-fold increase in the chance of HBP. In both sexes, excessive adolescent weight was associated with HBP (ORs, 3.5 and 5.0, for female and male adolescents, respectively). A higher fat mass index and fat-free mass index in female (ORs, 1.4 and 1.2, respectively) and male adolescents (ORs, 2.5 and 3.0, respectively) increased the chance of HBP. Among male adolescents, the chance of HBP was higher among those with rapid weight gain between 48 months and 6 years and between 6 and 11 years and rapid height gain between 6 and 11 years. Higher fat mass in both sexes and rapid weight gain in male adolescents are risk factors for HBP in adolescents aged 15 years, potentially amenable to prevention.


Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets.
Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits. Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed. Compared with engineered vascular conduits formed without external stabilization, glue membrane-stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers. Our technique reduces the production time of self-assembled, cell sheet-derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation.


Methods for describing the electromagnetic properties of silver and gold nanoparticles.
This Account provides an overview of the methods that are currently being used to study the electromagnetics of silver and gold nanoparticles, with an emphasis on the determination of extinction and surface-enhanced Raman scattering (SERS) spectra. These methods have proven to be immensely useful in recent years for interpreting a wide range of nanoscience experiments and providing the capability to describe optical properties of particles up to several hundred nanometers in dimension, including arbitrary particle structures and complex dielectric environments (adsorbed layers of molecules, nearby metal films, and other particles). While some of the methods date back to Mie's celebrated work a century ago, others are still at the forefront of algorithm development in computational electromagnetics. This Account gives a qualitative description of the physical and mathematical basis behind the most commonly used methods, including both analytical and numerical methods, as well as representative results of applications that are relevant to current experiments. The analytical methods that we discuss are either derived from Mie theory for spheres or from the quasistatic (Gans) model as applied to spheres and spheroids. In this discussion, we describe the use of Mie theory to determine electromagnetic contributions to SERS enhancements that include for retarded dipole emission effects, and the use of the quasistatic approximation for spheroidal particles interacting with dye adsorbate layers. The numerical methods include the discrete dipole approximation (DDA), the finite difference time domain (FDTD) method, and the finite element method (FEM) based on Whitney forms. We discuss applications such as using DDA to describe the interaction of two gold disks to define electromagnetic hot spots, FDTD for light interacting with metal wires that go from particle-like plasmonic response to the film-like transmission as wire dimension is varied, and FEM studies of electromagnetic fields near cubic particles.


Versailles Project on Advanced Materials and Standards interlaboratory study on intensity calibration for x-ray photoelectron spectroscopy instruments using low-density polyethylene.
We report the results of a Versailles Project on Advanced Materials and Standards interlaboratory study on the intensity scale calibration of x-ray photoelectron spectrometers using low-density polyethylene (LDPE) as an alternative material to gold, silver, and copper. An improved set of LDPE reference spectra, corrected for different instrument geometries using a quartz-monochromated Al Kα x-ray source, was developed using data provided by participants in this study. Using these new reference spectra, a transmission function was calculated for each dataset that participants provided. When compared to a similar calibration procedure using the NPL reference spectra for gold, the LDPE intensity calibration method achieves an absolute offset of ∼3.0% and a systematic deviation of ±6.5% on average across all participants. For spectra recorded at high pass energies (≥90 eV), values of absolute offset and systematic deviation are ∼5.8% and ±5.7%, respectively, whereas for spectra collected at lower pass energies (<90 eV), values of absolute offset and systematic deviation are ∼4.9% and ±8.8%, respectively; low pass energy spectra perform worse than the global average, in terms of systematic deviations, due to diminished count rates and signal-to-noise ratio. Differences in absolute offset are attributed to the surface roughness of the LDPE induced by sample preparation. We further assess the usability of LDPE as a secondary reference material and comment on its performance in the presence of issues such as variable dark noise, x-ray warm up times, inaccuracy at low count rates, and underlying spectrometer problems. In response to participant feedback and the results of the study, we provide an updated LDPE intensity calibration protocol to address the issues highlighted in the interlaboratory study. We also comment on the lack of implementation of a consistent and traceable intensity calibration method across the community of x-ray photoelectron spectroscopy (XPS) users and, therefore, propose a route to achieving this with the assistance of instrument manufacturers, metrology laboratories, and experts leading to an international standard for XPS intensity scale calibration.


[Cortexin and cortagen as correcting agents in functional and metabolic disorders in the brain in chronic ischemia].
The polypeptide drug cortexin and the synthetic peptide drug cortagen accelerate the recovery of disturbed individual behavior of ischemic rats with different resistance to hypoxia (high and low resistant rats). In addition, both drugs prevented an excessive activation of lipid peroxidation and a decrease in the antioxidant activity in the brain tissues. The obtained results suggest that cortexin and cortagen can be used for increasing the efficacy of neuroprotective therapy in cases of chronic brain ischemia.


Adherence to a new oral anticoagulant treatment prescription: dabigatran etexilate.
The recent development of new oral anticoagulants, of which dabigatran etexilate is currently at the most advanced stage of development, is the greatest advance in the provision of convenient anticoagulation therapy for many years. A new oral anticoagulation treatment, dabigatran etexilate, is already on the market in Europe. The main interest probably will be to improve the prescription and the adherence to an effective thromboprophylaxis in medical conditions such as atrial fibrillation without bleeding side effects, without the need for monitoring coagulation, and without drug and food interactions such as vitamin K anticoagulant (VKA) treatment. Dabigatran is particularly interesting for extended thromboprophylaxis after major orthopedic surgery in order to avoid daily injection for a month. However, oral long-term treatments such as VKA are not systematically associated with a higher compliance level than injected treatments such as low-molecular-weight heparins. Indeed, adherence to an oral treatment, instead of the usual daily injection in major orthopedic surgery, is complex, and based not only on the frequency of dosing but also on patient motivation, understanding, and socio-economic status. New oral anticoagulants may be useful in this way but education and detection of risk factors of nonadherence to treatment are still essential.


Chemical and Biological Aspects of Marine Sponges from the Family Mycalidae.
Sponges are a useful source of bioactive natural products. Members of the family Mycalidae, in particular, have provided a variety of chemical structures including alkaloids, polyketides, terpene endoperoxides, peptides, and lipids. This review highlights the compounds isolated from Mycalid sponges and their associated biological activities. A diverse group of 190 compounds have been reported from over 40 specimens contained in 49 references. Over half of the studies have reported on the biological activities for the compounds isolated. The polyketides, in particular the macrolides, displayed potent cytotoxic activities (< 1 µM), and the alkaloids, in particular the 2,5-disubstituted pyrrole derivatives, were associated with moderate cytotoxic activities (1-20 µM). The pyrrole alkaloids and the cyclic peroxides appear to be phylogenetically restricted to sponges and thus might prove useful when applied to sponge taxonomy. The observed diversity of chemical structures suggests this family makes a good target for targeted biodiscovery projects.


Bioactive nano-fibrous scaffold for vascularized craniofacial bone regeneration.
There has been a growing demand for bone grafts for correction of bone defects in complicated fractures or tumours in the craniofacial region. Soft flexible membrane like material that could be inserted into defect by less invasive approaches; promote osteoconductivity and act as a barrier to soft tissue in growth while promoting bone formation is an attractive option for this region. Electrospinning has recently emerged as one of the most promising techniques for fabrication of extracellular matrix such as nano-fibrous scaffolds that can serve as a template for bone formation. To overcome the limitation of cell penetration of electrospun scaffolds and improve on its osteoconductive nature, in this study, we fabricated a novel electrospun composite scaffold of polyvinyl alcohol (PVA)-poly (ε) caprolactone (PCL)-Hydroxyapatite based bioceramic (HAB), namely, PVA-PCL-HAB. The scaffold prepared by dual electrospinning of PVA and PCL with HAB overcomes reduced cell attachment associated with hydrophobic PCL by combination with a hydrophilic PVA and the HAB can contribute to enhance osteoconductivity. We characterized the physicochemical and biocompatibility properties of the new scaffold material. Our results indicate PVA-PCL-HAB scaffolds support attachment and growth of stromal stem cells; [human bone marrow skeletal (mesenchymal) stem cells and dental pulp stem cells]. In addition, the scaffold supported in vitro osteogenic differentiation and in vivo vascularized bone formation. Thus, PVA-PCL-HAB scaffold is a suitable potential material for therapeutic bone regeneration in dentistry and orthopaedics.


Iron-induced thrombocytopenia in severe iron-deficiency anemia.
Iron deficiency anemia (IDA) is commonly associated with reactive thrombocytosis, but thrombocytopenia is relatively uncommon and generally associated with more severe IDA. Even more rarely described has been thrombocytopenia following iron replacement therapy to treat IDA, and the underlying mechanism remains unclear. The authors present the case of a patient with severe IDA, who developed thrombocytopenia after the initiation of iron therapy. An analysis is made of all the previous reports of similar cases, to compare and start on the path of understanding this rare entity.


[Current occupational respiratory pathology in Switzerland].
The main features of occupational industrial respiratory diseases in Switzerland can be summarized as follows: -Silicosis: 9750 cases from 1930 to 1979. At present low annual incidence (less than 100 cases), age at first diagnosis over 40 years, at death almost 70 years. - Asbestosis: 130 cases from 1939 to 1979. 30 cases of mesothelioma (21 without asbestosis; 9 with), 9 of bronchial carcinoma and 1 of gastric cancer in the 130 cases of asbestosis. - Acute toxic lung (irritant gases such as chlorine, phosgene, nitrous gases), occupational asthma, extrinsic alveolitis and finally occupational chronic bronchitis are the principal diseases also observed.


Knowledge, attitudes, and practices of avian influenza among backyard poultry breeders in Fayoum Governorate, Egypt.
Avian influenza (H5N1) (AI) is becoming a serious public health threat in Egypt. The current study aimed to assess the existing knowledge, attitudes, and various practices regarding AI in household backyard poultry breeders residing in Fayoum Governorate, in rural Egypt. Of the 149 cases confirmed to date in Egypt, 51 have been fatal. This study was implemented in El Gendy and Manshat Abdllah villages in Fayoum Governorate. The latter village is the one in which a case of AI was confirmed in February 2007. A group of 150 women aged 15 years and above were recruited. A structured Arabic questionnaire was used to collect data. All interviewed women (N=150) had heard about AI. TV\radio was the common source of information (83.3%). Nearly all interviewed women knew that AI is transmitted from birds to humans (99%). Most of the participants (>90%) correctly identified saliva, nasal secretions, feces, and contaminated vehicles as the modes of AI transmission. The knowledge regarding biosecurity measures (>70%) and measures of prevention (>90%) was generally good. More than 90% of the interviewed housewives agreed that AI is a serious disease that can be prevented, and that sanitary precautions during breeding and food preparation practices are effective measures for prevention of AI infection. Protective measures such as the use of gloves and masks, which minimize the risk of transmission of AI from poultry to humans, were seldom used by housewives in all their breeding, slaughtering, and cooking practices. However, washing hands either with water or with soap and water was reported by the vast majority of the respondents (>90%). There was a good level of knowledge and favorable attitude of the study participants regarding AI; however, practices appear to be inadequate to achieve full protection against AI. Comprehensive and multidisciplinary interventions should be widely used to enhance the complex behavior change process among the village residents.


Relationship between natural killer cell activity and histological features of lymphocyte infiltration and partial regression of the primary tumor in melanoma patients.
A group of 194 melanoma patients with Stage I melanoma was studied in an attempt to correlate histological features of prognostic importance in malignant melanoma with the level of natural killer cell (NK) activity in blood mononuclear cells. Histological features examined were lymphocytic infiltrate of the tumor base, lymphocyte infiltration at the tumor margin, and evidence of partial regression in the tumor. NK activity against melanoma cells and non-melanoma cells was studied in the same patients before and after surgical removal of melanoma. Patients with high NK activity against melanoma and Chang cells had less lymphocyte infiltrate at the base of the tumor irrespective of its thickness than did those with low NK activity. Patients with low NK activity and thin tumors had more lymphocyte infiltration at the base of the tumor than did those with high NK activity. Similar results were obtained in certain subsets of cases with respect to lymphocytic infiltration at the tumor margins and to the presence of partial regression. Although the nature of the association between these histological features and NK activity in blood is unknown, it is suggested that previously unexplained associations between histological features and prognosis may be accounted for by their association with NK activity. If this proves to be correct, measurement of NK activity may be an important additional prognostic factor in patients with melanoma.


Parry Romberg Syndrome: 7 Cases and Literature Review.
Parry Romberg syndrome is a rare progressive hemiatrophy of the face that typically occurs in children and young adults and has a peculiar progression that ceases without apparent cause after a highly variable period. Only a subset of patients with Parry Romberg syndrome will develop secondary neurologic or ophthalmologic symptoms, and prognosis is highly variable. Inconsistency in the pattern of atrophy and the development of associated symptoms in patients with Parry Romberg syndrome has made it challenging to diagnose, prognosticate, and treat. The precise etiology of this disease remains unknown, but some authors have implicated sympathetic cervical ganglion dysfunction, abnormal embryogenesis, autoimmune and inflammatory mechanisms, or vasculopathy as potential causes. We present 7 cases of Parry Romberg syndrome and their associated clinical and imaging findings with specific attention to the radiographic characteristics of this disease.


Early onset heart failure in transgenic mice with dilated cardiomyopathy.
In children, dilated cardiomyopathy is due to a variety of etiologies and usually carries a grave prognosis. The purpose of the present study was to carefully follow the progression of events leading to cardiac dilatation and congestive heart failure in a dilated cardiomyopathy model in neonatal and juvenile mice. These initial steps are often not well characterized. Furthermore, the loss of gap junctions and reduced electrical coupling of cardiomyocytes frequently found in human cardiomyopathies are also observed in these early stages. By 2 wk of age, molecular markers associated with hypertrophy were already altered. Cardiomyocyte hypertrophy, reduced connexin43 expression, and decreased conduction velocity were apparent by 4 wk, before overt cardiac dysfunction (decreased shortening fraction and chamber remodeling) that was not present until 12 wk of age. Our results show that in this model cardiomyopathic changes are present by 2 wk after birth and progress rapidly during the subsequent 2 postnatal weeks. Combined with the observations of other models of heart disease, we suggest that the first 2 wk of postnatal life are absolutely critical for normal cardiac development, and events that perturb homeostasis during this period determine whether the heart will continue to develop normally. These animals exhibit early symptoms of disease including reduced connexin43 and conduction defects before impaired cardiac function and demonstrate for the first time a temporal association between decreased connexin43 levels and the initiation of a contractility deficit that ends in heart failure.


Overall vigilance and sustained attention decrements in healthy aging.
Age differences in sustained attention were investigated using a high-event rate digit-discrimination task at 6 levels of stimulus degradation (lasting 8.1 min each). Twenty-one young, 21 middle-aged, and 20 old healthy subjects were studied. Overall sensitivity (d') was equivalent in all groups. Although all subjects showed a sensitivity decrement over blocks, there were no age-related differences in sustained attention capacity. All subjects had larger decrements in d' over blocks at higher degradation levels. However, the performance decrement at higher degradation levels was equivalent in all groups, indicating similar decrement rates in sensitivity with increasing demands on effortful processing. These results indicate that overall levels of vigilance and the ability to sustain attention over time are equivalent in all groups under conditions requiring both automatic (low-degradation) and effortful (high-degradation) stimulus processing.


Population imaging of neural activity in awake behaving mice.
A longstanding goal in neuroscience has been to image membrane voltage across a population of individual neurons in an awake, behaving mammal. Here we describe a genetically encoded fluorescent voltage indicator, SomArchon, which exhibits millisecond response times and is compatible with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable several-fold over previously published fully genetically encoded reagents1-8. Under conventional one-photon microscopy, SomArchon enables the routine population analysis of around 13 neurons at once, in multiple brain regions (cortex, hippocampus, and striatum) of head-fixed, awake, behaving mice. Using SomArchon, we detected both positive and negative responses of striatal neurons during movement, as previously reported by electrophysiology but not easily detected using modern calcium imaging techniques9-11, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examined how spikes relate to the subthreshold theta oscillations of individual hippocampal neurons, with SomArchon showing that the spikes of individual neurons are more phase-locked to their own subthreshold theta oscillations than to local field potential theta oscillations. Thus, SomArchon reports both spikes and subthreshold voltage dynamics in awake, behaving mice.


Multifrequency control of Faraday wave patterns.
We show how pattern formation in Faraday waves may be manipulated by varying the harmonic content of the periodic forcing function. Our approach relies on the crucial influence of resonant triad interactions coupling pairs of critical standing wave modes with damped, spatiotemporally resonant modes. Under the assumption of weak damping and forcing, we perform a symmetry-based analysis that reveals the damped modes most relevant for pattern selection, and how the strength of the corresponding triad interactions depends on the forcing frequencies, amplitudes, and phases. In many cases, the further assumption of Hamiltonian structure in the inviscid limit determines whether the given triad interaction has an enhancing or suppressing effect on related patterns. Surprisingly, even for forcing functions with arbitrarily many frequency components, there are at most five frequencies that affect each of the important triad interactions at leading order. The relative phases of those forcing components play a key role, sometimes making the difference between an enhancing and suppressing effect. In numerical examples, we examine the validity of our results for larger values of the damping and forcing. Finally, we apply our findings to one-dimensional periodic patterns obtained with impulsive forcing and to two-dimensional superlattice patterns and quasipatterns obtained with multifrequency forcing.


Injectable silicone for facial soft-tissue augmentation.
Medical-grade injectable silicone has been safely and efficiently used for facial soft-tissue augmentation in 235 patients. Our 20-year experience with the microdroplet technique included 2,811 treatments performed for camouflaging furrows and grooves, augmentation of facial eminences, and elevation of certain depressed scars. The indications and techniques of injection are discussed. The augmenting effect is greater than that produced by the small volumes of silicone injected. Our study supports other work indicating induction of collagen deposition in the patients around the microdroplets of silicone, thus providing augmentation from volumes of collagen and silicone as well.


Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial.
To examine whether use of vitamins B(12), B(6), and folate was associated with reduced severity of depressive symptoms and 2-year incidence of clinically significant depression. The investigators recruited 299 men aged 75 years and older free of clinically significant depression (Beck Depression Inventory [BDI] score < 18). They were randomly assigned to treatment with 400 microg B(12) + 2 mg folic acid + 25 mg B(6) per day (N = 150) or placebo (N = 149). The BDI was the primary outcome measure of the study. Follow-up assessments took place 6, 12, 18, and 24 months after baseline. Analyses were intention-to-treat. The study was conducted from June 2001 to June 2004. 118 and 123 men treated with vitamins and placebo, respectively, completed this 2-year trial (19.4% dropout rate). Analysis of variance for repeated measures showed that there was no difference between the groups (F = 0.76, df = 1, p = .384) nor was there a significant change of BDI scores over time (F = 1.26, df = 4, p = .284). Cox regression revealed that participants treated with vitamins were 24% more likely to remain free of depression during the trial, although the difference between groups was not significant (95% CI = 0.68 to 2.28). At the end of the study, 84.3% of men treated with vitamins and 79.1% of those treated with placebo remained free of clinically significant depressive symptoms. The number of people needed to treat to show benefit was 21. The results of this study showed that treatment with B(12), folic acid, and B(6) is no better than placebo at reducing the severity of depressive symptoms or the incidence of clinically significant depression over a period of 2 years in older men. www.anzctr.org.au Identifier: ACTRN012605000045617.


Improving compliance with therapeutic regimens in hypertensive patients in a community health center.
A 1-year, randomized study was conducted to test the possibility of improving compliance with therapeutic regimens in hypertensives by means of certain simple arrangements. Patients were given written treatment instructions concerning hypertension, a personal blood-pressure follow-up card, and, for those who failed to attend their blood-pressure check-up, an invitation for a new check-up. Using matched pairs, 202 Finnish hypertensives were randomly allocated either to an ordinary or a reorganized treatment group. By means of the latter system, patient compliance could be significantly (p less than 0.01) improved: Only 4% of the patients in this group dropped out of treatment, compared with 19% in the ordinary treatment group. By the end of the year, blood pressure had been lowered by at least 10% in 95% of the patients in the reorganized group and in 78% of those in the ordinary group (p less than 0.01). This was achieved in approximately 60% of cases using chlorthalidone alone.