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The phylogeny of permanent prostate brachytherapy

Thu, 05/15/2014 - 5:14pm

Permanent prostate brachytherapy has been practiced for more than a century. This review examines the influence of earlier procedures on the modern transperineal ultrasound-directed technique. A literature review was conducted to examine the origin of current clinical practice. The dimensions of the modern brachytherapy seed, the prescription dose, and implant/teletherapy sequencing are vestigial features, which may be suboptimal in the current era of low-energy photon-emitting radionuclides and computerized dose calculations. Although the modern transperineal permanent prostate implant procedure has proven to be safe and effective, it should undergo continuous re-evaluation and evolution to ensure that its potential is maximized.

Coexisting intrarenal arteriovenous and caliceovenous fistulae after percutaneous nephrolithotomy: Case report and literature review

Thu, 05/15/2014 - 5:14pm

A 58-year-old man was re-admitted to the Urology service with delayed gross hematuria and unstable he-modynamics, following a percutaneous nephrolithotomy (PCNL) procedure performed for an obstructive solitary left lower calyceal stone. A selective left renal angiogram demonstrated an interpolar arteriovenous fistula (AVF), which was treated with successful coil embolization of a sub-segmental feeding branch. Sub-sequent nephrostogram confirmed a coexisting caliceovenous fistula, which was observed and healed spon-taneously. Iatrogenic coexisting intrarenal AVF and caliceovenous fistulae have never been reported and should be considered as a possible cause of delayed severe hematuria with unstable hemodynamics, and/or increase in baseline creatinine after PCNL.

Educating psychiatry residents in neuropsychiatry and neuroscience

Thu, 05/15/2014 - 5:14pm

Neuropsychiatry and psychiatric neuroscience should be part of the general psychiatry curriculum so that graduate psychiatrists will be able to allow their patients the benefit of neuroscientifically informed diagnosis and treatment. Current neurology and neuroscience educational requirements for US psychiatry training are reviewed. The draft milestone requirements for clinical neuroscience training as part of the US Accreditation Council for Graduate Medical Education's Next Accreditation System are also provided. Suggestions for the neuropsychiatric and neuroscience content of psychiatry residency training are made, along with a description of pedagogic methods and resources. Survey data are reviewed indicating agreement by programme directors with the importance of neuroscience training and an increase in the amount of time devoted to this area. Faculty staff development in neuropsychiatry and neuroscience literacy will be needed to provide high quality training in these areas.

Treating hypertension in patients with left ventricular dysfunction: hitting the fairway and avoiding the rough

Thu, 05/15/2014 - 5:14pm

Hypertension is a major risk factor in the development of heart failure (HF), yet current guidelines do not specify a target blood pressure (BP) for patients with established systolic or diastolic left ventricular (LV) dysfunction. While no randomized controlled trial (RCT) has been conducted to specify the optimal blood pressure in these patients, numerous trials have demonstrated the benefits of certain classes of medications and treatment strategies in patients with HF. Important factors to consider in treating hypertension in patients with HF include the type of HF (reduced vs. preserved ejection fraction), the etiology (ischemic vs. nonischemic), the severity of symptoms if any, the baseline blood pressure, as well as a wide variety of patient-specific factors. This paper reviews current evidence to address the question, "What should be the blood pressure goal in patients with asymptomatic and symptomatic left ventricular dysfunction?" We suggest a target blood pressure of 120-140/70-90 mm Hg in most cases, with lower pressures generally preferable if tolerated.

Improved image quality and detection of small cerebral infarctions with diffusion-tensor trace imaging

Thu, 05/15/2014 - 5:14pm

OBJECTIVE: The purpose of this study was to test a hypothesis that routinely performed diffusion-tensor trace imaging is of sufficient image quality and sensitivity for infarct detection to safely and routinely replace standard diffusion-weighted imaging (DWI) in the clinical setting.

MATERIALS AND METHODS: Both routine DWI and 15-direction diffusion-tensor imaging (DTI) with parallel acquisition technique were obtained on all brain MRI studies from a single 1.5-T MRI scanner at a tertiary care referral center over a 1-year period, permitting direct comparison of the two different diffusion studies on the same patients (2537 studies, 365 infarct-positive studies). A subset of images was assessed for image quality and quantitatively for ability to detect brain infarctions. The total set of positive studies was reviewed qualitatively for ability to detect small cerebral infarctions.

RESULTS: Fifteen-direction isotropic DWI (DTI trace images) with parallel acquisition technique resulted in consistently higher image quality with less distortion and higher image detail than routine DWI. Small infarcts were better seen, and in 12 cases, infarcts could only be seen on 15-direction isotropic diffusion-weighted images. The additional scanning time required for 15-direction isotropic DWI did not result in significantly increased motion-related reduction in image quality compared with standard DWI.

CONCLUSION: Diffusion-tensor trace images obtained with parallel acquisition technique are of improved image quality and improved sensitivity for detection of small cerebral infarctions relative to standard DWI. If such DTI data are acquired, routine DWI can be omitted.

Adipocyte lineages: tracing back the origins of fat

Thu, 05/15/2014 - 5:14pm

The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

The normalcy of dormancy: common themes in microbial quiescence

Thu, 05/15/2014 - 5:14pm

All microorganisms are exposed to periodic stresses that inhibit growth. Many bacteria and fungi weather these periods by entering a hardy, nonreplicating state, often termed quiescence or dormancy. When this occurs during an infection, the resulting slowly growing pathogen is able to tolerate both immune insults and prolonged antibiotic exposure. While the stresses encountered in a free-living environment may differ from those imposed by host immunity, these growth-limiting conditions impose common pressures, and many of the corresponding microbial responses appear to be universal. In this review, we discuss the common features of these growth-limited states, which suggest new approaches for treating chronic infections such as tuberculosis.

Adipose tissue angiogenesis: impact on obesity and type-2 diabetes

Thu, 05/15/2014 - 5:14pm

The growth and function of tissues are critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data points to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Breastfeeding During Early Infancy is Associated with a Lower Incidence of Febrile Illnesses

Thu, 05/15/2014 - 5:14pm

Human breast milk is known to contain immunoprotective, antimicrobial, and anti-inflammatory agents. In a prospective clinical study of dengue virus infections during infancy, we examined the correlation between breastfeeding and the development of febrile illnesses in an infant population. We found that breastfeeding status and the frequency of breastfeeding during early infancy was associated with a lower incidence of febrile illnesses.

(De-) oiling inflammasomes

Thu, 05/15/2014 - 5:14pm

Activation of inflammasome signaling can produce harmful inflammation. In this issue of Immunity, Yan et al. (2013) suggest that omega-3 fatty acids commonly found in marine oils can suppress activation of NLRP3 and NLRP1b inflammasomes.

Breastfeeding During Early Infancy is Associated with Higher Weight-Based World Health Organization Anthropometry

Thu, 05/15/2014 - 5:14pm

The World Health Organization (WHO) Expert Committee on Physical Status: The Use and Interpretation of Anthropometry established reference anthropometric standards for the growth of healthy infants and children. As part of a prospective clinical study of dengue virus infections in infants, we measured the length and weight of healthy infants in San Pablo, Laguna, Philippines at two scheduled study visits. We examined the correlation between breastfeeding and WHO anthropometric z scores during early infancy in San Pablo, Laguna, Philippines. We found that breastfeeding status and the frequency of breastfeeding during early infancy positively correlated with weight-based WHO anthropometric z scores.

Nucleosome dynamics regulates DNA processing

Thu, 05/15/2014 - 5:14pm

The repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity. The first step in DSB repair by homologous recombination is the processing of the ends by one of two resection pathways, executed by the Saccharomyces cerevisiae Exo1 and Sgs1-Dna2 machineries. Here we report in vitro and in vivo studies that characterize the impact of chromatin on each resection pathway. We find that efficient resection by the Sgs1-Dna2-dependent machinery requires a nucleosome-free gap adjacent to the DSB. Resection by Exo1 is blocked by nucleosomes, and processing activity can be partially restored by removal of the H2A-H2B dimers. Our study also supports a role for the dynamic incorporation of the H2A.Z histone variant in Exo1 processing, and it further suggests that the two resection pathways require distinct chromatin remodeling events to navigate chromatin structure.

Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

Thu, 05/15/2014 - 5:14pm

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.

A single pair of interneurons commands the Drosophila feeding motor program

Thu, 05/15/2014 - 5:13pm

Many feeding behaviours are the result of stereotyped, organized sequences of motor patterns. These patterns have been the subject of neuroethological studies, such as electrophysiological characterization of neurons governing prey capture in toads. However, technical limitations have prevented detailed study of the functional role of these neurons, a common problem for vertebrate organisms. Complexities involved in studies of whole-animal behaviour can be resolved in Drosophila, in which remote activation of brain cells by genetic means enables us to examine the nervous system in freely moving animals to identify neurons that govern a specific behaviour, and then to repeatedly target and manipulate these neurons to characterize their function. Here we show neurons that generate the feeding motor program in Drosophila. We carried out an unbiased screen using remote neuronal activation and identified a critical pair of brain cells that induces the entire feeding sequence when activated. These 'feeding neurons' (here abbreviated to Fdg neurons for brevity) are also essential for normal feeding as their suppression or ablation eliminates sugar-induced feeding behaviour. Activation of a single Fdg neuron induces asymmetric feeding behaviour and ablation of a single Fdg neuron distorts the sugar-induced feeding behaviour to become asymmetric, indicating the direct role of these neurons in shaping motor-program execution. Furthermore, recording neuronal activity and calcium imaging simultaneously during feeding behaviour reveals that the Fdg neurons respond to food presentation, but only in starved flies. Our results demonstrate that Fdg neurons operate firmly within the sensorimotor watershed, downstream of sensory and metabolic cues and at the top of the feeding motor hierarchy, to execute the decision to feed.

Inflammatory cytokine-mediated evasion of virus-induced tumors from NK cell control

Thu, 05/15/2014 - 5:13pm

Infections with DNA tumor viruses, including members of the polyomavirus family, often result in tumor formation in immune-deficient hosts. The complex control involved in antiviral and antitumor immune responses during these infections can be studied in murine polyomavirus (PyV)-infected mice as a model. We found that NK cells efficiently kill cells derived from PyV-induced salivary gland tumors in vitro in an NKG2D (effector cell)-RAE-1 (target cell)-dependent manner; but in T cell-deficient mice, NK cells only delay but do not prevent the development of PyV-induced tumors. In this article, we show that the PyV-induced tumors have infiltrating functional NK cells. The freshly removed tumors, however, lack surface RAE-1 expression, and the tumor tissues produce soluble factors that downregulate RAE-1. These factors include the proinflammatory cytokines IL-1alpha, IL-1beta, IL-33, and TNF. Each of these cytokines downregulates RAE-1 expression and susceptibility to NK cell-mediated cytotoxicity. CD11b(+)F4/80(+) macrophages infiltrating the PyV-induced tumors produce high amounts of IL-1beta and TNF. Thus, our data suggest a new mechanism whereby inflammatory cytokines generated in the tumor environment lead to evasion of NK cell-mediated control of virus-induced tumors.

Yeast Upf1 CH domain interacts with Rps26 of the 40S ribosomal subunit

Thu, 05/15/2014 - 5:13pm

The central nonsense-mediated mRNA decay (NMD) regulator, Upf1, selectively targets nonsense-containing mRNAs for rapid degradation. In yeast, Upf1 preferentially associates with mRNAs that are NMD substrates, but the mechanism of its selective retention on these mRNAs has yet to be elucidated. Previously, we demonstrated that Upf1 associates with 40S ribosomal subunits. Here, we define more precisely the nature of this association using conventional and affinity-based purification of ribosomal subunits, and a two-hybrid screen to identify Upf1-interacting ribosomal proteins. Upf1 coimmunoprecipitates specifically with epitope-tagged 40S ribosomal subunits, and Upf1 association with high-salt washed or puromycin-released 40S subunits was found to occur without simultaneous eRF1, eRF3, Upf2, or Upf3 association. Two-hybrid analyses and in vitro binding assays identified a specific interaction between Upf1 and Rps26. Using mutations in domains of UPF1 known to be crucial for its function, we found that Upf1:40S association is modulated by ATP, and Upf1:Rps26 interaction is dependent on the N-terminal Upf1 CH domain. The specific association of Upf1 with the 40S subunit is consistent with the notion that this RNA helicase not only triggers rapid decay of nonsense-containing mRNAs, but may also have an important role in dissociation of the premature termination complex.

A mutation in the stalk of the newcastle disease virus hemagglutinin-neuraminidase (HN) protein prevents triggering of the F protein despite allowing efficient HN-F complex formation

Thu, 05/15/2014 - 5:13pm

Newcastle disease virus (NDV)-induced membrane fusion requires formation of a complex between the hemagglutinin-neuraminidase (HN) and fusion (F) proteins. Substitutions for NDV HN stalk residues A89, L90, and L94 block fusion by modulating formation of the HN-F complex. Here, we demonstrate that a nearby L97A substitution, though previously shown to block fusion, allows efficient HN-F complex formation and likely acts by preventing changes in the HN stalk required for triggering of the bound F protein.

Body enhancement through female genital cosmetic surgery creates ethical and rights dilemmas

Thu, 05/15/2014 - 5:13pm

Female genital cosmetic surgery is surgery performed on a woman within a normal range of variation of human anatomy. The issues are heightened by a lack of long-term and substantive evidence-based literature, conflict of interest from personal financial gain through performing these procedures, and confusion around macroethical and microethical domains. It is a source of conflict and controversy globally because the benefit and harm of offering these procedures raise concerns about harmful cultural views, education, and social vulnerability of women with regard to both ethics and human rights. The rights issues of who is defining normal female anatomy and function, as well as the economic vulnerability of women globally, bequeath the profession a greater responsibility to ensure that there is adequate health and general education-not just among patients but broadly in society-that there is neither limitation nor interference in the decision being made, and that there are no psychological disorders that could be influencing such choices. Published by Elsevier Ireland Ltd. All rights reserved.

Humanized mice for the study of infectious diseases

Thu, 05/15/2014 - 5:13pm

Many of the pathogens that cause human infectious diseases do not infect rodents or other mammalian species. Small animal models that allow studies of the pathogenesis of these agents and evaluation of drug efficacy are critical for identifying ways to prevent and treat human infectious diseases. Immunodeficient mice engrafted with functional human cells and tissues, termed 'humanized' mice, represent a critical pre-clinical bridge for in vivo studies of human pathogens. Recent advances in the development of humanized mice have allowed in vivo studies of multiple human infectious agents providing novel insights into their pathogenesis that was otherwise not possible.