Michael Bennett

Newborn screening for metabolic diseases was initially introduced in the 1960s with a program for the early diagnosis of phenylketonuria. Guidelines for the introduction of additional conditions to the screen required that the condition was sufficiently common to merit screening, that it was treatable and that the cost of diagnosis was not prohibitive. Additional conditions added to the screen included congenital hypothyroidism and congenital adrenal hyperplasia. The recognition of medium-chain acyl0CoA dehydrogenase deficiency coupled to the advent of tandem mass spectrometry as a diagnostic tool allowed for the inclusion of many more conditions into screening programs, some of which do not fit the original criteria for inclusion. This presentation will discuss the current state of newborn screening for metabolic diseases and report on clinical outcome measures of patients identified by screening.

Mitochondrial respiratory chain (RC) disease diagnosis is complicated both by an absence of biomarkers that sufficiently divulge all cases and limited capacity to quantify adverse effects across intermediary metabolism. We applied high performance liquid chromatography (HPLC) and mass spectrometry (MS) studies of stable-isotope based precursor-product relationships in the nematode, C. elegans, to interrogate in vivo differences in metabolic flux among distinct genetic models of primary RC defects and closely related metabolic disorders. C. elegans strains studied harbor single nuclear gene defects in complex I, II, or III RC subunits (gas-1, mev-1, isp-1); enzymes involved in coenzyme Q biosynthesis (clk-1), the tricarboxylic acid cycle (TCA, idh-1), or pyruvate metabolism (pdha-1); and central nodes of the nutrient-sensing signaling network that involve insulin response (daf-2) or the sirtuin homologue (sir-2.1). Synchronous populations of 2000 early larval stage worms were fed standard Escherichia coli on nematode growth media plates containing 1,6-(13)C2-glucose throughout their developmental period, with samples extracted on the first day of adult life in 4% perchloric acid with an internal standard. Quantitation of whole animal free amino acid concentrations and isotopic incorporation into amino and organic acids throughout development was performed in all strains by HPLC and isotope ratio MS, respectively. GC/MS analysis was also performed to quantify absolute isotopic incorporation in all molecular species of key TCA cycle intermediates in gas-1 and N2 adult worms. Genetic mutations within different metabolic pathways displayed distinct metabolic profiles. RC complex I (gas-1) and III (isp-1) subunit mutants, together with the coenzyme Q biosynthetic mutant (clk-1), shared a similar amino acid profile of elevated alanine and decreased glutamate. The metabolic signature of the complex II mutant (mev-1) was distinct from that of the other RC mutants but resembled that of the TCA cycle mutant (idh-1) and both signaling mutants (daf-2 and sir-2.1). All branched chain amino acid levels were significantly increased in the complex I and III mutants but decreased in the PDH mutant (pdha-1). The RC complex I, coenzyme Q, TCA cycle, and PDH mutants shared significantly increased relative enrichment of lactate+1 and absolute concentration of alanine+1, while glutamate+1 enrichment was significantly decreased uniquely in the RC mutants. Relative intermediary flux analyses were suggestive of proximal TCA cycle disruption in idh-1, completely reduced TCA cycle flux in sir-2.1, and apparent distal TCA cycle alteration in daf-2. GC/MS analysis with universally-labeled (13)C-glucose in adult worms further showed significantly increased isotopic enrichment in lactate, citrate, and malate species in the complex I (gas-1) mutant. Stable isotopic/mass spectrometric analysis can sensitively discriminate primary RC dysfunction from genetic deficiencies affecting either the TCA cycle or pyruvate metabolism. These data are further suggestive that metabolic flux analysis using stable isotopes may offer a robust means to discriminate and quantify the secondary effects of primary RC dysfunction across intermediary metabolism.

Neuropathic pain (NP) in cancer patients lacks standards for diagnosis. This study is aimed at reaching consensus on the application of the International Association for the Study of Pain (IASP) special interest group for neuropathic pain (NeuPSIG) criteria to the diagnosis of NP in cancer patients and on the relevance of patient-reported outcome (PRO) descriptors for the screening of NP in this population. An international group of 42 experts was invited to participate in a consensus process through a modified 2-round Internet-based Delphi survey. Relevant topics investigated were: peculiarities of NP in patients with cancer, IASP NeuPSIG diagnostic criteria adaptation and assessment, and standardized PRO assessment for NP screening. Median consensus scores (MED) and interquartile ranges (IQR) were calculated to measure expert consensus after both rounds. Twenty-nine experts answered, and good agreement was found on the statement "the pathophysiology of NP due to cancer can be different from non-cancer NP" (MED=9, IQR=2). Satisfactory consensus was reached for the first 3 NeuPSIG criteria (pain distribution, history, and sensory findings; MEDs⩾8, IQRs⩽3), but not for the fourth one (diagnostic test/imaging; MED=6, IQR=3). Agreement was also reached on clinical examination by soft brush or pin stimulation (MEDs⩾7 and IQRs⩽3) and on the use of PRO descriptors for NP screening (MED=8, IQR=3). Based on the study results, a clinical algorithm for NP diagnostic criteria in cancer patients with pain was proposed. Clinical research on PRO in the screening phase and on the application of the algorithm will be needed to examine their effectiveness in classifying NP in cancer patients.

It is proven that if a;b and c are positive integers then the simul- taneous Diophantine equations ax 2 by 2 =1 ;b y 2 cz 2 =1 possess at most one solution in positive integers (x;y;z). The proof utilizes estimates for linear forms in logarithms of algebraic numbers.

`Energy auditing’ as a technique for obtaining a ‘snapshot’ of the energy flows in a city or urban conurbation is discussed in the context of meeting national and international targets for CO2 emissions abatement. An audit methodology is presented which addresses the key questions: Who needs to be involved in the audit? How should the city or conurbation be divided? What data are required? How might these data be obtained and then analysed? Which are the areas of significant consumption? A basis for setting local targets for reducing future energy consumption and CO2 emissions is presented. The scope for auditing major cities and conurbations in the United Kingdom is identified with reference to implementing Local Agenda 21 and satisfying CO2 emissions reduction targets.

Human plasma α 1-acid glycoprotein (orosomucoid) and derivatives of this protein produced by sequential enzymatic cleavage of the glycosidic residues (sialic acid, galactose, N-acetylglucosamine, mannose) were tested for the ability to suppress a number of immune functions of mouse spleen cells in vitro at physiological concentrations. α 1-Acid glycoprotein and especially the agalacto/asialo derivative suppressed (i) the mitogenic responses to concanavalin A, lipopolysaccharide, and alloantigens, (ii) antibody responses to sheep erythrocytes, and (iii) induction of cell-mediated lympholysis against allogeneic target cells. The native protein and its derivative did not inhibit the proliferation of EL-4 lymphoma cells and did not suppress the lysis of YAC-1 lymphoma cells by natural killer cells. The enhanced potency of the agalacto/asialo derivative indicates that the nature of the carbohydrate moiety exposed on the protein determines the effectiveness of the glycoprotein. The results suggest that α 1-acid glycoprotein and its deglycosylated derivatives may function to regulate immune responses in various physiological and pathological conditions.

Until July of 1992, the maximum length of the Bevalac flattop was 2 seconds, limiting the beam spill to 1.5 seconds. The normal running condition was a 1.5 second flattop, with a 1.0 second beam spill. If we define the duty factor as the spill length (in time) divided by the synchrotron pulse length, that is, the percentage of time the Bevalac can deliver beam to experiments, the duty factor for the 1.5 second flattop ranged from 17% (at full field, i.e., 12575 G) to 25% (low field). The purpose of the Long Flattop Project was to increase the length of the flattop, thus increasing the duty factor of the machine, and its efficiency for experiments. This has been done, with resultant increase in the duty factor and experimental data rate. It is now possible to run with duty factor of about 80% for low fields, falling to about 60% at 10 kG, and 34% at full field. This report documents what was done, and its limitations. It should be noted that increasing the length of the beam spill is only possible if the source can produce more beam per pulse than is usable by the experimenter. Experimenters running at full intensity with a short flattop (1.5 seconds) cannot benefit from a longer flattop. This paper describe the changes that have been made to Bevalac systems to make the long flattop possible, the limits put on the length of the flattop by existing hardware, and the procedure for tuning for the long flattop.

Investigation and control of flow phenomena in the pneumatic conveying of solids requires a detailed knowledge on the flow regimes and a number of phase flow properties. Electrical capacitance tomography (ECT) is shown here to be a robust tool for this purpose, particularly when dense phase plug flow is to be monitored. The application of ECT to dense phase powder conveying in an experimental vacuum system is demonstrated and described, including the visualisation of slug size, shape and velocity. Measured gas and solid flow rates were also analysed in an attempt to ultimately provide a basis for comprehensive on-line analysis. A number of statistical estimators were selected and used in data processing, in order to distinguish between particular types of dense flow. The results show the potential for use of the method for the on-line control of dense phase pneumatic conveyors.

Natural killer cells are bone marrow-derived lymphocytes capable of lysing a variety of target cells without prior exposure. While the biological activities and function of mature NK cells have been extensively investigated, the differentiation of NK cells from primitive hematopoietic stem cells is poorly understood. Recently, we have reported on the identification of a highly enriched bone marrow population capable of repopulating recipient mice with mature NK cells. In this review, we will summarize our findings and those of others in an attempt to clarify the current status of murine natural killer cell differentiation.

... Center for Etectronic Materiats and Processing, The Pennsylvania State University, University Park, Pennsylvania 16802 M. Bennett Sotarex Thin ... charge-limited currents of holes have been obtained in intrinsic hydrogenated amorphous silicon layers using pip structures and ...

As a powerful research tool, siRNA's therapeutic and target validation utility with leukemia cells and long-term gene knockdown is severely restricted by the lack of omnipotent, safe, stable, and convenient delivery. Here, we detail our discovery of siRNA-containing lipid nanoparticles (LNPs) able to effectively transfect several leukemia and difficult-to-transfect adherent cell lines also providing in vivo delivery to mouse spleen and bone marrow tissues through tail-vein administration. We disclose a series of novel structurally related lipids accounting for the superior transfection ability, and reveal a correlation between expression of Caveolins and successful transfection. These LNPs, bearing low toxicity and long stability of >6 months, are ideal for continuous long-term dosing. Our discovery represents the first effective siRNA-containing LNPs for leukemia cells, which not only enables high-throughput siRNA screening with leukemia cells and difficult-to-transfect adherent cells but also paves the way for the development of therapeutic siRNA for leukemia treatment.

BackgroundNonsteroidal anti-inflammatory drug (NSAID) gastropathy is recognized as a major cause of hospitalizations and deaths, with more than 100,000 annual hospitalizations and more than 10,000 annual deaths in the United States alone. Trends in this epidemic over time have not been examined.ObjectiveWe studied the possibility that new preventive approaches to NSAID gastropathy may have reduced the magnitude of this epidemic.MethodsWe studied 5598 patients with rheumatoid arthritis from longitudinal data banks previously employed to help establish the epidemiology of NSAID gastropathy. Consecutively enrolled patients were followed with bi-annual Health Assessment Questionnaire assessments and medical record audits between 1981 and 2000. Annual rates of hospitalization involving gastrointestinal (GI) bleeding, obstruction, or perforation were calculated and curves fitted using spline regression.ResultsAnnual GI hospitalization rates rose from 0.6% in 1981 to a peak of 1.5% in 1992, t ...

Caring for and caring about people with dementia require specific communication skills. Healthcare professionals and family caregivers usually receive little training to enable them to meet the communicative needs of people with dementia. This review identifies existent interventions to enhance communication in dementia care in various care settings. We searched MEDLINE, AMED, EMBASE, PsychINFO, CINAHL, The Cochrane Library, Gerolit, and Web of Science for scientific articles reporting interventions in both English and German. An intervention was defined as communication skills training by means of face-to-face interaction with the aim of improving basic communicative skills. Both professional and family caregivers were included. The effectiveness of such training was analyzed. Different types of training were defined. Didactic methods, training content, and additional organizational features were qualitatively examined. This review included 12 trials totaling 831 persons with dementia, 519 professional caregivers, and 162 family caregivers. Most studies were carried out in the USA, the UK, and Germany. Eight studies took place in nursing homes; four studies were located in a home-care setting. No studies could be found in an acute-care setting. We provide a list of basic communicative principles for good communication in dementia care. Didactic methods included lectures, hands-on training, group discussions, and role-play. This review shows that communication skills training in dementia care significantly improves the quality of life and wellbeing of people with dementia and increases positive interactions in various care settings. Communication skills training shows significant impact on professional and family caregivers' communication skills, competencies, and knowledge. Additional organizational features improve the sustainability of communication interventions.

... Quaternary Geology of Alameda County, and Parts of Contra Costa, Santa Clara, San Mateo, San Francisco, Stanislaus, and San Joaquin Counties, California, A Digital Database, US Geol. Surv. ... Tinsley, JC, Egan, JA, Kayen, RE, Bennett, MJ, Kropp, A., and Holzer, TL, 1998. ...

The authors present a case of severe megaloblastic anemia and neurologic damage due to vitamin B12 deficiency in a 6-month-old infant. The cause of the vitamin deficiency was a maternal dietary deficiency because of a strict vegetarian diet and prolonged breast-feeding. The importance of early recognition of significant maternal vitamin B12 deficiency during pregnancy and lactation in vegetarians is emphasized so that appropriate supplementation can be given and irreversible neurologic damage in the infant prevented.

Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in women whose fetuses are later found to have a deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase. This enzyme resides in the mitochondrial trifunctional protein, which also contains the active site of long-chain 2,3-enoyl-CoA hydratase and long-chain 3-ketoacyl-CoA thiolase. We undertook this study to determine the relation between mutations in the trifunctional protein in infants with defects in fatty-acid oxidation and acute liver disease during pregnancy in their mothers. In 24 children with 3-hydroxyacyl-CoA dehydrogenase deficiency, we used DNA amplification and nucleotide-sequence analyses to identify mutations in the alpha subunit of the trifunctional protein. We then correlated the results with the presence of liver disease during pregnancy in the mothers. Nineteen children had a deficiency only of long-chain 3-hydroxyacyl-CoA dehydrogenase and presented with hypoketotic hypoglycemia and fatty liver. In eight children, we identified a homozygous mutation in which glutamic acid at residue 474 was changed to glutamine. Eleven other children were compound heterozygotes, with this mutation in one allele of the alpha-subunit gene and a different mutation in the other allele. While carrying fetuses with the Glu474Gln mutation, 79 percent of the heterozygous mothers had fatty liver of pregnancy or the HELLP syndrome. Five other children, who presented with neonatal dilated cardiomyopathy or progressive neuromyopathy, had complete deficiency of the trifunctional protein (loss of activity of all three enzymes). None had the Glu474Gln mutation, and none of their mothers had liver disease during pregnancy. Women with acute liver disease during pregnancy may have a Glu474Gln mutation in long-chain hydroxyacyl-CoA dehydrogenase. Their infants are at risk for hypoketotic hypoglycemia and fatty liver.

... Shana Agid Shana Agid is Assistant Professor of Art, Media + Technology at Parsons the New School for Design, teaching design research, writing, and book arts. Shana is a Radical Teacher board member and the journal's art director. ... Davis, Angela Y. Are Prisons Obsolete? ...