Influence of scatter reduction method and monochromatic beams on image quality and dose in mammography.

In mammography, the image contrast and dose delivered to the patient are determined by the x-ray spectrum and the scatter to primary ratio S/P. Thus the quality of the mammographic procedure is highly dependent on the choice of anode and filter material and on the method used to reduce the amount of scattered radiation reaching the detector. Synchrotron radiation is a useful tool to study the effect of beam energy on the optimization of the mammographic process because it delivers a high flux of monochromatic photons. Moreover, because the beam is naturally flat collimated in one direction, a slot can be used instead of a grid for scatter reduction. We have measured the ratio S/P and the transmission factors for grids and slots for monoenergetic synchrotron radiation. In this way the effect of beam energy and scatter rejection method were separated, and their respective importance for image quality and dose analyzed. Our results show that conventional mammographic spectra are not far from optimum and that the use of a slot instead of a grid has an important effect on the optimization of the mammographic process. We propose a simple numerical model to quantify this effect.

Anterior subluxation after reduction of a posterior traumatic sterno-clavicular dislocation: a case report and a review of the literature.

Sternoclavicular dislocations represent a rare injury. Based on our clinical experience with a patient showing an anterior subluxation after reduction of a posterior traumatic dislocation, we review the literature. The emergent reduction of the dislocation is mandatory, always keeping in mind the potentially devastating neurovascular complications. If the treatment of a residual anterior instability remains controversial, a residual posterior instability should be treated by a surgical procedure. The optimal treatment depends mainly on each surgeon's choice and practice.

A genetic basis for functional hypothalamic amenorrhea.

Background: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. Methods: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. Results: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. Conclusions: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.)

The effect of exercise, alcohol or both combined on health and physical performance.

Alcohol (ethanol) is consumed on a daily basis by a large fraction of the population, and in many countries, light-to-moderate alcohol consumption is considered as an integral part of the diet. Although the relationship between alcohol intake and obesity is controversial, regular consumption of alcohol, through its effects in suppressing fat oxidation, is regarded as a risk factor for weight gain, increased abdominal obesity and hypertriglyceridemia. Indeed, alcohol taken with a meal leads to an increase in postprandial lipemia-an effect on postprandial metabolism that is opposite to that observed with exercise. Furthermore, although regular exercise training and/or a preprandial exercise session reduce postprandial lipemia independently of alcohol ingestion, the exercise-induced reduction in postprandial lipemia is nonetheless less pronounced when alcohol is also consumed with the meal. Whether or not alcohol influences exercise and sport performance remains contradictory. It is believed that alcohol has deleterious effects on the performance, although it may contribute to reduce pain and anxiety. The alcohol effects on sports performance depend on the type and dosage of alcohol, acute vs chronic administration, the alcohol elimination rate as well as the type of exercise.

Intentional risk reduction practices of men in Switzerland who have anal intercourse with casual male partners.

OBJECTIVE: To identify prevalence of and factors associated with intentional use of HIV risk reduction practices by men who have sex with men during anal intercourse with casual partners. METHODS: Cross-sectional survey pertaining to the Swiss HIV behavioral surveillance system, using an anonymous self-administered questionnaire in a self-selected sample of men who have sex with men (n = 2953). Multinomial regression was used to estimate factors associated with reporting either "no or inconsistent condom use" or "one or more risk reduction practices" over "consistent condom use." RESULTS: 57.2% reported anal intercourse with casual partner(s) over the last 12 months. Of these, 24.0% declared having used a risk reduction practice (73.8% of those who did not use condoms consistently). HIV-positive people were more likely to have done so. Most predictors were similarly associated to both regression categories. Four significant predictors were common to both regression categories: Internet partner seeking, age, age squared, and the interaction between HIV status positive and number of partners. The only association that differed markedly between the 2 regression categories was having a number of partners above median, significantly associated with the risk reduction category. CONCLUSIONS: Although condom use is the most frequent protection strategy in anal intercourse with casual partners, risk reduction practices are highly prevalent. However, there are no clear differences regarding predictors between risk reduction practices and inconsistent or no condom use. This suggests that risk reduction is an opportunistic response rather than a strategy per se.

Adipose reduction in the activity of the repressor ICER is responsible for insulin resistance elicited by the transcriptional factors CREB in obesity

BACKGROUND AND AIMS: Sustained adipose activation of the transcriptional activators cAMP response binding proteins (CREB) in obesity leads to impaired expression of the glucose transporter GLUT4 and adiponectin (adipoq) in mice model of obesity. Diminution of GLUT4 and adipoq caused by CREB is indirect and relies on the increased repressive activity of the CREB target gene activating transcription factor 3 (ATF3). Specific inactivation of CREB in adipocytes decreases ATF3 production and improves whole-body insulin sensitivity of mice in the context of diet-induced obesity. Thus, elevation of CREB activity is a key mechanism responsible for adipocyte dysfunction and systemic insulin resistance. The inducible cAMP early repressor (ICER) is a negative regulator of the CREB activity. In fact, ICER antagonizes the CREB factor by competing for the regulation of similar target genes. The goal of the study was to investigate whether loss of ICER expression in adipocytes could be responsible for increased CREB activity in obesity. MATERIALS AND METHODS: Mice C57bl6 were fed with a high fat diet (HFD) for 12 weeks to increase body weight and generate insulin resistance. Biopsies of visceral adipose tissues (VAT) were prepared from human lean (BMI=24}0.5 Kg/m2) or obese subjects (BMI>35 Kg/m2). Total RNA and protein were prepared from white adipose tissues (WAT) of chow- or HFD-fed mice and VAT of lean and obese subjects. Activities of CREBs and ICER were monitored by electromobility shift assays (EMSA). The role of ICER on CREB activity was confirmed in 3T3-L1 adipocytes cells. Briefly after differentiation, the cells were electroporated with the plasmid coding for ICER cDNA. Gene expression was quantified by quantitative real-time PCR and western Blotting experiments. RESULTS: The expression of ICER is reduced in WAT of HFD-induced obese mice when compared to chow mice as measured by real-time PCR and EMSA. Similar result was found in human tissues. Reduction in ICER expression was associated with increased ATF3 expression and decreased adipoq and GLUT4 contents. Diminution in ICER levels was observed in adipocytes fraction whereas its expression was unchanged in stroma vascular fraction of WAT. Overexpression of ICER in 3T3-L1 adipocytes silenced the expression of ATF3, confirming the regulation of the factor by ICER. The expression of ICER is regulated by histone deacetylases activity (HDAC). Inhibition of HDACs in 3T3-L1 adipocytes cells using trichostatin inhibited the production of ICER. The whole activity of HDAC was reduced in WAT and VAT of obese mice and human obese subjects. CONCLUSION: Impaired adipose expression of ICER is responsible of increased CREB activity in adipocytes in obesity. This mechanism relies on reduction of the HDAC activity.

Intravitreal Dexamethasone Implant for the Treatment of Macular Edema after Retinal Vein Occlusion in a Clinical Setting.

Background: To study the efficacy and safety of a new intravitreal implant (sustained release of dexamethasone, Ozurdex®) recently approved in Switzerland for the treatment of macular edema secondary to retinal vein occlusion in a clinical setting.Patients and Methods: Prospective non-consecutive study of patients with macular edema secondary to central retinal vein occlusion or branch retinal vein occlusion treated with implant of dexamethasone 0.7 mg. Follow-up visits were performed at day 1, week 1 and monthly thereafter. ETDRS best corrected visual acuity, Goldmann tonometry and macular thickness on SD-OCT were registered. Retreatment was carried out on a pro re nata basis starting from month 3.Results: Fifteen eyes of 15 patients were included (8 branch retinal vein occlusions, 7 central retinal vein occlusions). 33 % of the patients achieved 3 lines or more of vision gain. The central retinal vein occlusion subgroup showed a mean decline in visual acuity at month 3. A reduction of 36 % of macular edema was already observed at day 1. All maculae were dry at month 1. The mean time of recurrence of macular edema for both groups was 4.6 months. A similar reduction of macular edema was obtained after a second implantation. An intraocular pressure increase of ≥ 20 % was observed after the first implantation in 53 % of patients.Conclusion: Our study showed efficacy and safety of intravitreal dexamethasone implant in the treatment of macular edema due to retinal vein occlusion. Anatomical efficacy was observed at day 1 but seems to have shorter effect than previously published data. No serious side effects were observed.

Reduction of choroidal neovascularization in mice by adeno-associated virus-delivered anti-vascular endothelial growth factor short hairpin RNA.

BACKGROUND: Strategies leading to the long-term suppression of inappropriate ocular angiogenesis are required to avoid the need for repetitive monthly injections for treatment of diseases of the eye, such as age-related macular degeneration (AMD). The present study aimed to develop a strategy for the sustained repression of vascular endothelial growth factor (VEGF), which is identified as the key player in exudative AMD. METHODS: We have employed short hairpin (sh)RNAs combined with adeno-associated virus (AAV) delivery to obtain the targeted expression of potent gene-regulatory molecules. Anti-VEGF shRNAs were analyzed in human retinal pigment epithelial (RPE) cells using Renilla luciferase screening. For in vivo delivery of the most potent shRNA, self-complementary AAV vectors were packaged in serotype 8 capsids (scAAV2/8-hU6-sh9). In vivo efficacy was evaluated either by injection of scAAV2/8-hU6-sh9 into murine hind limb muscles or in a laser-induced murine model of choroidal neovascularization (CNV) following scAAV2/8-hU6-sh9 subretinal delivery. RESULTS: Plasmids encoding anti-VEGF shRNAs showed efficient knockdown of human VEGF in RPEs. Intramuscular administration led to localized expression and 91% knockdown of endogenous murine (m)VEGF. Subsequently, the ability of AAV2/8-encoded shRNAs to impair vessel formation was evaluated in the murine model of CNV. In this model, the sizes of the CNV were significantly reduced (up to 48%) following scAAV2/8-hU6-sh9 subretinal delivery. CONCLUSIONS: Using anti-VEGF vectors, we have demonstrated efficient silencing of endogenous mVEGF and showed that subretinal administration of scAAV2/8-hU6-sh9 has the ability to impair vessel formation in an AMD animal model. Thus, AAV-encoded shRNA can be used for the inhibition of neovascularization, leading to the development of sustained anti-VEGF therapy. Copyright © 2012 John Wiley & Sons, Ltd.

Enchondromatosis revisited: New classification with molecular basis.

The so-called "enchondromatoses" are skeletal disorders defined by the presence of ectopic cartilaginous tissue within bone tissue. The clinical and radiographic features of the different enchondromatoses are distinct, and grouping them does not reflect a common pathogenesis but simply a similar radiographic appearance and thus the need for a differential diagnosis. Recent advances in the understanding of their molecular and cellular bases confirm the heterogeneous nature of the different enchondromatoses. Some, like Ollier disease, Maffucci disease, metaphyseal chondromatosis with hydroxyglutaric aciduria, and metachondromatosis are produced by a dysregulation of chondrocyte proliferation, while others (such as spondyloenchondrodysplasia or dysspondyloenchondromatosis) are caused by defects in structure or metabolism of cartilage or bone matrix. In other forms (e.g., the dominantly inherited genochondromatoses), the basic defect remains to be determined. The classification, proposed by Spranger and associates in 1978 and tentatively revised twice, was based on the radiographic appearance, the anatomic sites involved, and the mode of inheritance. The new classification proposed here integrates the molecular genetic advances and delineates phenotypic families based on the molecular defects. Reference radiographs are provided to help in the diagnosis of the well-defined forms. In spite of advances, many cases remain difficult to diagnose and classify, implying that more variants remain to be defined at both the clinical and molecular levels. © 2012 Wiley Periodicals, Inc.

An evaluation of the inorganic and organic geochemistry of the San Vicente Mississippi Valley-type zinc-lead district, central Peru: Implications for ore fluid composition, mixing processes, and sulfate reduction

Mississippi Tialley-type zinc-lead deposits and ore occurrences in the San Vicente belt are hosted in dolostones of the eastern Upper Triassic to Lower Jurassic Pucara basin, central Peru. Combined inorganic and organic geochemical data from 22 sites, including the main San Vicente deposit, minor ore occurrences, and barren localities, provide better understanding of fluid pathways and composition, ore precipitation mechanisms, Eh-pH changes during mineralization, and relationships between organic matter and ore formation. Ore-stage dark replacement dolomite and white sparry dolomite are Fe and rare earth element (REE) depleted, and Mn enriched, compared to the host dolomite. In the main deposit, they display significant negative Ce and probably Eu anomalies. Mixing of an incoming hot, slightly oxidizing, acidic brine (H2CO3 being the dominant dissolved carbon species), probably poor in REE and Fe, with local intraformational, alkaline, reducing waters explains the overall carbon and oxygen isotope variation and the distributions of REE and other trace elements in the different hydrothermal carbonate generations. The incoming ore fluid flowed through major aquifers, probably basal basin detrital units, with limited interaction with the carbonate host rocks. The hydrothermal carbonates show a strong regional chemical homogeneity, indicating access of the ore fluids by interconnected channelways near the ore occurrences. Negative Ce anomalies in the main deposit, that are absent at the district scale, indicate local ore-fluid chemical differences. Oxidation of both migrated and indigenous hydrocarbons by the incoming fluid provided the local reducing conditions necessary for sulfate reduction to H2S, pyrobitumen precipitation, and reduction of Eu3+ to Eu2+. Fe-Mn covariations, combined with the REE contents of the hydrothermal carbonates, are consistent with the mineralizing system shifting from reducing/rock-dominated to oxidizing/fluid-dominated conditions following ore deposition. Sulfate and sulfide sulfur isotopes support sulfide origin from evaporite-derived sulfate by thermochemical organic reduction; further evidence includes the presence of C-13-depleted calcite cements (similar to-12 parts per thousand delta(13)C) as sulfate pseudomorphs, elemental sulfur, altered organic matter in the host dolomite, and isotopically heavier, late, solid bitumen. Significant alteration of the indigenous and extrinsic hydrocarbons, with absent bacterial membrane biomarkers (hopanes) is observed. The light delta(34)S of sulfides from small mines and occurrences compared to the main deposit reflect a local contribution of isotopically light sulfur, evidence of local differences in the ore-fluid chemistry.

Towards the identification of a genetic basis for Landau-Kleffner syndrome.

OBJECTIVE: To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. METHODS: We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. RESULTS: A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. SIGNIFICANCE: A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Reduction of ARNT in myeloid cells causes immune suppression and delayed wound healing.

Aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor that binds to partners to mediate responses to environmental signals. To investigate its role in the innate immune system, floxed ARNT mice were bred with lysozyme M-Cre recombinase animals to generate lysozyme M-ARNT (LAR) mice with reduced ARNT expression. Myeloid cells of LAR mice had altered mRNA expression and delayed wound healing. Interestingly, when the animals were rendered diabetic, the difference in wound healing between the LAR mice and their littermate controls was no longer present, suggesting that decreased myeloid cell ARNT function may be an important factor in impaired wound healing in diabetes. Deferoxamine (DFO) improves wound healing by increasing hypoxia-inducible factors, which require ARNT for function. DFO was not effective in wounds of LAR mice, again suggesting that myeloid cells are important for normal wound healing and for the full benefit of DFO. These findings suggest that myeloid ARNT is important for immune function and wound healing. Increasing ARNT and, more specifically, myeloid ARNT may be a therapeutic strategy to improve wound healing.