Bone infection: a clinical priority for clinicians, scientists and educators.

Bone infection has received increasing attention in recent years as one of the main outstanding clinical problems in orthopaedic-trauma surgery that has not been successfully addressed. In fact, infection may develop across a spectrum of patient types regardless of the level of perioperative management, including antibiotic prophylaxis. Some of the main unknown factors that may be involved, and the main targets for future intervention, include more accurate and less invasive diagnostic options, more thorough and accurate debridement protocols, and more potent and targeted antimicrobials. The underlying biology dominates the clinical management of bone infections, with features such as biofilm formation, osteolysis and vascularisation being particularly influential. Based on the persistence of this problem, an improved understanding of the basic biology is deemed necessary to enable innovation in the field. Furthermore, from the clinical side, better evidence, documentation and outreach will be required to translate these innovations to the patient. This review presents the findings and progress of the AO Trauma Clinical Priority Program on the topic of bone infection.

Modernizing and Expanding the NASA Space Geodesy Network to Meet Future Geodetic Requirements.

NASA maintains and operates a global network of Very Long Baseline Interferometry (VLBI), Satellite Laser Ranging (SLR), and Global Navigation Satellite System (GNSS) ground stations as part of the NASA Space Geodesy Program. The NASA Space Geodesy Network (NSGN) provides the geodetic products that support Earth observations and the related science requirements as outlined by the US National Research Council (NRC 2010, 2018). The Global Geodetic Observing System (GGOS) and the NRC have set an ambitious goal of improving the Terrestrial Reference Frame (TRF) to have an accuracy of 1 millimeter and stability of 0.1 millimeters per year, an order of magnitude beyond current capabilities. NASA and its partners within GGOS are addressing this challenge by planning and implementing modern geodetic stations co-located at existing and new sites around the world. In 2013, NASA demonstrated the performance of its next-generation systems at the prototype next-generation core site at NASA's Goddard Geophysical and Astronomical Observatory in Greenbelt, Maryland. Implementation of a new broadband VLBI station in Hawaii was completed in 2016. NASA is currently implementing new VLBI and SLR stations in Texas and is planning the replacement of its other aging domestic and international legacy stations. In this article, we describe critical gaps in the current global network and discuss how the new NSGN will expand the global geodetic coverage and ultimately improve the geodetic products. We also describe the characteristics of a modern NSGN site and the capabilities of the next-generation NASA SLR and VLBI systems. Finally, we outline the plans for efficiently operating the NSGN by centralizing and automating the operations of the new geodetic stations.

Metabolic inflexibility of white and brown adipose tissues in abnormal fatty acid partitioning of type 2 diabetes.

Type 2 diabetes (T2D) is characterized by a general dysregulation of postprandial energy substrate partitioning. Although classically described in regard to glucose metabolism, it is now evident that metabolic inflexibility of plasma lipid fluxes is also present in T2D. The organ that is most importantly involved in the latter metabolic defect is the white adipose tissue (WAT). Both catecholamine-induced nonesterified fatty acid mobilization and insulin-stimulated storage of meal fatty acids are impaired in many WAT depots of insulin-resistant individuals. Novel molecular imaging techniques now demonstrate that these defects are linked to increased dietary fatty acid fluxes toward lean organs and myocardial dysfunction in humans. Recent findings also demonstrate functional abnormalities of brown adipose tissues in T2D, thus suggesting that a generalized adipose tissue dysregulation of energy storage and dissipation may be at play in the development of lean tissue energy overload and lipotoxicity.

Hypercholesterolaemia, signs of islet microangiopathy and altered angiogenesis precede onset of type 2 diabetes in the Goto-Kakizaki (GK) rat.

AIMS/HYPOTHESIS: The adult non-obese Goto-Kakizaki (GK) rat model of type 2 diabetes, particularly females, carries in addition to hyperglycaemia a genetic predisposition towards dyslipidaemia, including hypercholesterolaemia. As cholesterol-induced atherosclerosis may be programmed in utero, we looked for signs of perinatal lipid alterations and islet microangiopathy. We hypothesise that such alterations contribute towards defective pancreas/islet vascularisation that might, in turn, lead to decreased beta cell mass. Accordingly, we also evaluated islet inflammation and endothelial activation in both prediabetic and diabetic animals. METHODS: Blood, liver and pancreas were collected from embryonic day (E)21 fetuses, 7-day-old prediabetic neonates and 2.5-month-old diabetic GK rats and Wistar controls for analysis/quantification of: (1) systemic variables, particularly lipids; (2) cholesterol-linked hepatic enzyme mRNA expression and/or activity; (3) pancreas (fetuses) or collagenase-isolated islet (neonates/adults) gene expression using Oligo GEArray microarrays targeted at rat endothelium, cardiovascular disease biomarkers and angiogenesis, and/or RT-PCR; and (4) pancreas endothelial immunochemistry: nestin (fetuses) or von Willebrand factor (neonates). RESULTS: Systemic and hepatic cholesterol anomalies already exist in GK fetuses and neonates. Hyperglycaemic GK fetuses exhibit a similar percentage decrease in total pancreas and islet vascularisation and beta cell mass. Normoglycaemic GK neonates show systemic inflammation, signs of islet pre-microangiopathy, disturbed angiogenesis, collapsed vascularisation and altered pancreas development. Concomitantly, GK neonates exhibit elevated defence mechanisms. CONCLUSIONS/INTERPRETATION: These data suggest an autoinflammatory disease, triggered by in utero programming of cholesterol-induced islet microangiopathy interacting with chronic hyperglycaemia in GK rats. During the perinatal period, GK rats show also a marked deficient islet vascularisation in conjunction with decreased beta cell mass.

Homocysteine threshold value based on cystathionine beta synthase and paraoxonase 1 activities in mice.

BACKGROUND: Hyperhomocysteinaemia is a metabolic disorder associated with the development of premature atherosclerosis. Among the determinants which predispose to premature thromboembolic and atherothrombotic events, serum activity of paraoxonase 1, mainly synthesized in the liver, has been shown to be a predictor of cardiovascular disease and to be negatively correlated with serum homocysteine levels in human. Even though treatments of hyperhomocysteinaemic patients ongoing cardiovascular complications are commonly used, it still remains unclear above which homocysteine level a preventive therapy should be started. MATERIALS AND METHODS: In order to establish a threshold of plasma homocysteine concentration we have analyzed the hepatic cystathionine beta synthase and paraoxonase 1 activities in a moderate to intermediate murine model of hyperhomocysteinaemia. Using wild type and heterozygous cystathionine beta synthase deficient mice fed a methionine enriched diet or a control diet, we first studied the link between cystathionine beta synthase and paraoxonase 1 activities and plasma homocysteine concentration. RESULTS: Among the animals used in this study, we observed a negative correlation between plasma homocysteine level and cystathionine beta synthase activity (rho=-0.52, P=0.0008) or paraoxonase 1 activity (rho=-0.49, P=0.002). Starting from these results, a homocysteine cut-off value of 15 microm has been found for both cystathionine beta synthase (P=0.0003) and paraoxonase 1 (P=0.0007) activities. CONCLUSIONS: Our results suggest that both cystathionine beta synthase and paraoxonase 1 activities are significantly decreased in mice with a plasma homocysteine value greater than 15 microm. In an attempt to set up preventive treatment for cardiovascular disease our results indicate that treatments should be started from 15 microm of plasma homocysteine.

Molecular cloning and functional expression of two splice forms of human N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase.

We have isolated and sequenced human cDNA and mouse genomic DNA clones encoding N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase (phosphodiester alpha-GlcNAcase) which catalyzes the second step in the synthesis of the mannose 6-phosphate recognition signal on lysosomal enzymes. The gene is organized into 10 exons. The protein sequence encoded by the clones shows 80% identity between human and mouse phosphodiester alpha-GlcNAcase and no homology to other known proteins. It predicts a type I membrane-spanning glycoprotein of 514 amino acids containing a 24-amino acid signal sequence, a luminal domain of 422 residues with six potential N-linked glycosylation sites, a single 27-residue transmembrane region, and a 41-residue cytoplasmic tail that contains both a tyrosine-based and an NPF internalization motif. Human brain expressed sequence tags lack a 102-base pair region present in human liver cDNA that corresponds to exon 8 in the genomic DNA and probably arises via alternative splicing. COS cells transfected with the human cDNA expressed 50-100-fold increases in phosphodiester alpha-GlcNAcase activity proving that the cDNA encodes the subunits of the tetrameric enzyme. Transfection with cDNA lacking the 102-base pair region also gave active enzyme. The complete genomic sequence of human phosphodiester alpha-GlcNAcase was recently deposited in the data base. It showed that our cDNA clone was missing only the 5'-untranslated region and initiator methionine and revealed that the human genomic DNA has the same exon organization as the mouse gene.

Lipid-laden alveolar macrophages (LLAM): a useful marker of silent aspiration in children.

At present there is no test available which identifies children suffering from silent aspiration due to gastroesophageal reflux (GER). The purpose of this study was to determine whether lipid-laden alveolar macrophage (LLAM) scoring is a useful method to arrive at the diagnosis. We evaluated bronchoalveolar lavage fluid (BALF) from 68 children aged 6 months to 14 years (median 3.75 years) for the presence of lipid-laden alveolar macrophages. We compared children with chronic chest disease (CCD) and GER to healthy surgical controls without known lung disease, and to children with recurrent pneumonia without GER. By grading the amount of intracellular Sudan Red-positive material, we determined a semiquantitative lipid-laden macrophage (LLAM) score for each patient. Patients with chronic chest disease suspected to be caused by silent aspiration secondary to GER had a significantly higher LLAM score (median, 117; range, 10-956) than children with recurrent pneumonia due to other reasons (median, 29; range, 5-127; P < 0.01) and healthy controls (median, 37; range, 5-188; P < 0.01). We believe that simply observing lipid-laden macrophages is nonspecific, but quantitation of these cells is a useful method for diagnosing silent aspiration in children, especially when the score exceeds 200.

Purification and multimeric structure of bovine N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase.

N-Acetylglucosamine-1-phosphodiester alpha-N-Acetylglucosaminidase (EC 3.1.4.45; phosphodiester alpha-GlcNAcase) catalyzes the second step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome. A partially purified preparation of phosphodiester alpha-GlcNAcase from bovine pancreas was used to generate a panel of murine monoclonal antibodies. The anti-phosphodiester alpha-GlcNAcase monoclonal antibody UC1 was coupled to a solid support and used to immunopurify the bovine liver enzyme 670,000-fold in two steps to apparent homogeneity with an overall yield of 14%. The purified phosphodiester alpha-GlcNAcase has a specific activity of 498 micromol of [3H]GlcNAc-alpha-phosphomannose-alpha-methyl cleaved per h per mg of protein using 0.5 mM [3H]GlcNAc-alpha-phosphomannose-alpha-methyl as substrate. The subunit structure of the enzyme was determined using a combination of analytical gel filtration chromatography, SDS-polyacrylamide gel electrophoresis, and amino-terminal sequencing. The data indicate that bovine phosphodiester alpha-GlcNAcase is a 272,000-Da complex of four identical 68,000-Da glycoprotein subunits arranged as two disulfide-linked homodimers. A soluble form of the enzyme, isolated from fetal bovine serum, showed the same subunit structure. Both forms of the enzyme reacted with a rabbit antibody raised to the amino-terminal peptide of the liver enzyme, suggesting that phosphodiester alpha-GlcNAcase is a type I membrane-spanning glycoprotein with its amino terminus in the lumen of the Golgi apparatus.

Alcohol abuse in the elderly.

Alcoholism is often difficult to recognize in the elderly. Information about alcoholic behavior cannot always be accurately extrapolated to older drinkers. Consequences of alcohol abuse and responses to treatment may be quite different in young and elderly alcoholics. Treatment must focus on such day-to-day problems as loneliness, loss of independence and declining health. Gentle persistence is required in guiding the patient to an awareness of the problem.

Anorexia and weight loss in the elderly. Causes range from loose dentures to debilitating illness.

Differentiating between anorexia (loss of appetite) and weight loss (documented loss of pounds) can be difficult, but the same causes and treatments apply to both. Gastrointestinal and metabolic disorders, cardiopulmonary disease, the presence of a neoplasm or infection, and use of certain drugs are possible medical causes. Inadequate nutritional intake can result from the inability to obtain and prepare foods, dietary restrictions, intolerance to certain foods, and poor oral and dental health. Social factors that can greatly reduce an elderly person's interest in food include loneliness, depression, isolation, and self-consciousness because of hearing and visual impairments. Some problems, such as alcohol abuse or inappropriate use of certain medications, may be revealed only with difficulty, and some of the problems mentioned may overlap. Although the physician may find assessment of anorexia or weight loss in the elderly a challenge, it usually responds well to corrective measures.

[Results of sling surgery using Tutoplast dura]. / Ergebnisse nach Schlingenoperation mit Tutoplast-Dura.

From 1976-1979 127 patients were treated with a tutoplast dura sling operation. Either an open or a closed sling was used. Between one and four and one half years later 117 patients were re-examined and 65 patients had urodynamic tests. The late results of tutoplast dura sling operations are good and compare favorably to the upper data indicated in the literature. The best results are obtained in cases of prolapse. The closed sling has higher success rates but also higher complication rates than the open sling. Primary operations have better results than operations for recurrence. A severe stress incontinence should be subjected to specific primary treatment.

How reliable is determination of ulcer size by endoscopy?

The suface areas of 23 artificial ulcers in a rubber manikin and of 35 ulcers in 35 consecutive patients admitted for endoscopy of the upper gastrointestinal tract were estimated by six endoscopists. Of the 138 estimations made in the manikin 80% underestimated the true size of the ulcer: the mean (+/- SD) was -29 +/- 40%. The largest and the smallest estimate of the same ulcer by different endoscopists varied on average by a factor of 4.5 +/- 3.8, and the estimates by the same endoscopists of ulcers with the same size varied by a factor of 2.3 +/- 0.6. In the patients the scatter of the estimates was even larger, the mean factor being 7.8 +/- 6.3. Changes in ulcer size are therefore an unsuitable criterion for assessing ulcer healing. Even if consecutive examinations are performed by the same endoscopist, changes in ulcer area smaller than by a factor of 3 are not discernible.