Changes in Myocardial Metabolism Preceding Sudden Cardiac Death.

Heart disease is widely recognized as a major cause of death worldwide and is the leading cause of mortality in the United States. Centuries of research have focused on defining mechanistic alterations that drive cardiac pathogenesis, yet sudden cardiac death (SCD) remains a common unpredictable event that claims lives in every age group. The heart supplies blood to all tissues while maintaining a constant electrical and hormonal feedback communication with other parts of the body. As such, recent research has focused on understanding how myocardial electrical and structural properties are altered by cardiac metabolism and the various signaling pathways associated with it. The importance of cardiac metabolism in maintaining myocardial function, or lack thereof, is exemplified by shifts in cardiac substrate preference during normal development and various pathological conditions. For instance, a shift from fatty acid (FA) oxidation to oxygen-sparing glycolytic energy production has been reported in many types of cardiac pathologies. Compounded by an uncoupling of glycolysis and glucose oxidation this leads to accumulation of undesirable levels of intermediate metabolites. The resulting accumulation of intermediary metabolites impacts cardiac mitochondrial function and dysregulates metabolic pathways through several mechanisms, which will be reviewed here. Importantly, reversal of metabolic maladaptation has been shown to elicit positive therapeutic effects, limiting cardiac remodeling and at least partially restoring contractile efficiency. Therein, the underlying metabolic adaptations in an array of pathological conditions as well as recently discovered downstream effects of various substrate utilization provide guidance for future therapeutic targeting. Here, we will review recent data on alterations in substrate utilization in the healthy and diseased heart, metabolic pathways governing cardiac pathogenesis, mitochondrial function in the diseased myocardium, and potential metabolism-based therapeutic interventions in disease.

Effects of health at every size® interventions on health-related outcomes of people with overweight and obesity: a systematic review.

CONTEXT: The growing use of interventions based on the Health at Every Size® (HAES®) in obesity management. OBJECTIVE: This study aimed to summarize the health-related effects of HAES®-based interventions on people with overweight and obesity. DATA SOURCES: MEDLINE (via PubMed), EMBASE, Cochrane Library, LILACS, Google Scholar, OpenGrey and Grey Literature Report. STUDY SELECTION: A systematic review of studies published until January 2017 reporting on HAES®-based randomized and non-randomized controlled trials in people with overweight and/or obesity. DATA EXTRACTION: Fourteen papers met the inclusion criteria. The assessed studies included the following tests: blood profile, blood pressure, anthropometry, eating behaviour, energy intake, diet quality, psychological and qualitative evaluations. RESULTS: The HAES® interventions benefited both the psychological and physical activity outcomes, besides promoting behavioural and qualitative changes in eating habits. On the other hand, the results regarding cardiovascular responses, body-image perception and total energy intake were inconsistent. CONCLUSIONS: Despite improving the cardiovascular status, eating behaviours, quality of life and psychological well-being in participants, other large long-term clinical trials should be performed to establish the effectiveness of HAES®-based interventions in improving health for people with overweight and obesity. PROSPERO registration 2017: CRD42017054857.

Implementation of B'More Healthy Communities for Kids: process evaluation of a multi-level, multi-component obesity prevention intervention.

B'More Healthy Communities for Kids was a multi-level, multi-component obesity prevention intervention to improve access, demand and consumption of healthier foods and beverages in 28 low-income neighborhoods in Baltimore City, MD. Process evaluation assesses the implementation of an intervention and monitor progress. To the best of our knowledge, little detailed process data from multi-level obesity prevention trials have been published. Implementation of each intervention component (wholesaler, recreation center, carryout restaurant, corner store, policy and social media/text messaging) was classified as high, medium or low according to set standards. The wholesaler component achieved high implementation for reach, dose delivered and fidelity. Recreation center and carryout restaurant components achieved medium reach, dose delivered and fidelity. Corner stores achieved medium reach and dose delivered and high fidelity. The policy component achieved high reach and medium dose delivered and fidelity. Social media/text messaging achieved medium reach and high dose delivered and fidelity. Overall, study reach and dose delivered achieved a high implementation level, whereas fidelity achieved a medium level. Varying levels of implementation may have balanced the performance of an intervention component for each process evaluation construct. This detailed process evaluation of the B'More Healthy Communities for Kids allowed the assessment of implementation successes, failures and challenges of each intervention component.

Partnering with carryouts: implementation of a food environment intervention targeting youth obesity.

Youth obesity is a major public health problem in the United States, especially among urban-based, minority youth. The B'More Healthy Communities for Kids (BHCK) trial worked at multiple levels of the food environment, including carryouts, to increase access to and demand for healthy, affordable foods. The objective of this article is to describe the development and implementation of BHCK's carryout intervention. Process evaluation was conducted to assess intervention reach (number of interactions with youth and adults either in person or on social media), dose delivered (number of food samples and promotional materials distributed, social media posts and meetings with owners) and fidelity (availability of promoted items). Overall, the carryout intervention showed moderate to optimal reach, moderate to optimal dose delivered and moderate to optimal fidelity. These findings demonstrate a successfully implemented carryout intervention in a low-income urban setting. Lessons learned about new methods for engaging the community and increasing demand for healthy food can be used to inform future studies and programs to improve the food environment.

Polymorphisms on IFNG, IL12B and IL12RB1 genes and paracoccidioidomycosis in the Brazilian population.

Paracoccidioidomycosis (PCM) is a systemic chronic mycosis, endemic in Latin America, especially Brazil, and is the eighth leading cause of death among chronic and recurrent infectious diseases. PCM infection is characterized by the presence of Th1 immune response; the acute form, by a mixed Th2/Th9, while the chronic form is characterized by Th17/Th22 profiles. The occurrence and severity of human PCM may also be associated with genetic factors such as single nucleotide polymorphisms (SNP) on cytokines encoding genes. We investigated the association between these polymorphisms and the different clinical forms of PCM. We included 156 patients with PCM (40 with the acute form, 99 with the chronic multifocal and 17 with the chronic unifocal form) and assayed their DNA samples for IFNG +874 T/A SNP by PCR-ARMS (Amplification Refractory Mutational System), IL12B +1188 A/C SNP on 3' UTR and IL12RB1 641 A/G SNP on exon 7 by PCR-RFLP (Restriction Fragment Length Polymorphism). We found similar genotypic and allelic frequencies of the investigated SNPs among the clinical forms of PCM. Considering male patients, the IL12RB1 641 AA genotype was more frequent in the chronic multifocal form while heterozygosis was in the chronic unifocal form of PCM (p=0.048). Although our data suggest that the AA genotype (IL12RB1) may be associated with the more disseminated chronic disease, more patients of the chronic unifocal PCM group need to be analyzed as well as the secretion patterns of IFN-γ combined with the IL-12Rß1 expression for a better comprehension of this association.

Characterization of monocyte-derived dendritic cells from patients with active and treated paracoccidioidomycosis.

Cellular immune responses are a significant defence mechanism in human paracoccidioidomycosis (PCM), an endemic mycosis in Latin America; however, little is known about the role of dendritic cells (DCs) in human PCM. We investigated monocyte-derived DCs from patients with treated (TP) and active PCM (AP) compared with healthy non-PCM donors (CO). DCs from the TP group showed higher expression of HLA-DR, CD86 and DC-SIGN compared with CO, whereas AP showed similar expression to CO. Production of IL-10 was downregulated by TNF-α in all groups and lower levels were observed in untreated DCs from AP compared with CO. Conversely, IL-12p40 was significantly upregulated in the DCs of the TP group. TNF-α-activated DCs from the CO group produced significantly lower levels of IL-12p40 when differentiated from magnetic-sorted monocytes (MACS) compared with adhered monocyte-derived DCs. This comparison in the TP group revealed similar levels of IL-12p40, suggesting a T cell-independent increase in the production of IL-12p40. Higher expression of surface molecules with increased IL-12p40 may indicate a better activation of DCs after the treatment of PCM. Our findings suggest that DCs may be crucial in the protective response to Paracoccidioides brasiliensis and that in vitro-generated DCs might be useful in enhancing antifungal immunity, especially during active PCM.

Subsite substrate specificity of midgut insect chymotrypsins.

Insect chymotrypsins are distinctively sensitive to plant protein inhibitors, suggesting that they differ in subsite architecture and hence in substrate specificities. Purified digestive chymotrypsins from insects of three different orders were assayed with internally quenched fluorescent oligopeptides with three different amino acids at P1 (Tyr, Phe, and Leu) and 13 amino acid replacements in positions P1', P2, and P3. The binding energy (DeltaG(s), calculated from K(m) values) and the activation energy (DeltaG(T)++, determined from k(cat)/K(m) values) were calculated. The hydrophobicities of each subsite were calculated from the efficiency of hydrolysis of the different amino acid replacements at that subsite. The results showed that except for S1, the other subsites (S2, S3, and S1') vary among chymotrypsins. This result contrasts with insect trypsin data that revealed a trend along evolution, putatively associated with resistance to plant inhibitors. In spite of those differences, the data suggested that in lepidopteran chymotrypsins S2 and S1' bind the substrate ground state, whereas only S1' binds the transition state, supporting aspects of the present accepted mechanism of catalysis.

Differences in the inhibition of translation by cisplatin, transplatin, and certain related compounds.

The non-therapeutic cisplatin congeners transplatin and chloroethylenetriamine platinum (dien) inhibited translation to a similar extent as cisplatin did. The IC50 values were: cisplatin 23 microM, transplatin 54 microM, and dien 117 microM. Unlike certain heavy metal inhibitors of translation, the effect of neither cisplatin nor the congeners was reversed by 3':5'-cyclic adenosine monophosphate (cAMP). This suggests that the effect of these platinum compounds does not occur by the heavy metal mechanism. Polyribosomes and ribosomal subunits formed in transplatin-inhibited reactions differed from those in reactions inhibited by cisplatin. Specifically, large polyribosomes and complete 80S ribosomal subunits accumulated in the presence of transplatin. This indicates that while cisplatin slowed initiation of peptide synthesis, the trans-isomer slowed elongation. Substantive differences were not found between cisplatin and the monofunctional compound dien. This congener increased the non-peptidyl disintegrations per minute in the acid precipitates of assays containing [35S]methionine. The high background indicated that an interaction between the label and a precipitable component of the system was induced by dien. However, consumption of methionine by this interaction did not appear to be the cause of the inhibition. Although there may be differences in the mechanisms of the effects, the finding that the non-therapeutic congeners inhibit translation at similar concentrations as cisplatin suggests that this inhibition is not responsible for the anticancer effect. On the other hand, the possibility that decreased translation could play an important role in the toxicity of these compounds in certain quiescent cells cannot be ruled out.

Prevention indicators for evaluating the progress of national AIDS programmes.

PIP: Major interventions to reduce HIV transmission involve increasing knowledge about preventing HIV transmission for sustained behavioral changes; and enhancing the control of sexually transmitted diseases (STD), which increase the probability of HIV transmission. Activities have also been developed to prevent the transmission of HIV by blood, donor selection, and more rational use of transfusions. Behavioral changes among injecting drug users have also been promoted. Recommendations are made for the evaluation of AIDS programs, focusing on prevention of sexual transmission of HIV, and outlining the approach developed by the Global Program on AIDS (GPA; Geneva, Switzerland) for use by national programs. Based on the feasibility, accuracy, reliability and validity of the quantitative assessment of programs, 10 indicators of progress and outcomes of prevention activities have been developed by GPA. These include indicators of population knowledge regarding preventive practices, reported sexual behavior and use of condoms in the general population, STD service evaluation, and indicators of program impact. The latter are measured through the reported STD incidence in the general male population, and syphilis and HIV prevalence in women. The four methods are proposed for measuring the 10 core prevention indicators (PI). Five PIs are measured during a population survey: reported knowledge of preventive practices (PI-1), condom availability at peripheral level (PI-3), reported frequency of nonregular sexual partners (PI-4), reported condom use during nonregular sexual encounters (PI-5), and reported STD incidence among men (PI-9). Condom availability at central level (PI-2) is assessed through key-informant interviews with major distributors. Structured health facility surveys allow assessment of the appropriateness of STD case management (PI-6 and PI-7). A serosurvey among antenatal clinic attenders aged 15-24 years allows the measurement of HIV and syphilis seroprevalence in that population (PI-8 and PI-10). GPA recommends that such surveys be repeated after a period of 1 to several years.^ieng

The global HIV pandemic.

The paper reviews the distribution, transmission patterns, and likely impacts of the HIV pandemic at the beginning of 1993. As of early 1993, a cumulative total of 611,589 cases of AIDS were reported to the World Health Organization (WHO); however, because of less than complete diagnosis and reporting, the WHO estimates that a total of 2.5 million cases of AIDS had actually occurred. As of early 1993, the WHO estimates that there have been approximately 13 million infections, of which about 1 million have been in children. By the year 2000 the WHO predicts that there will be 30-40 million cumulative infections in the world, of which 90% will be in developing countries and almost half will be among women. The epidemic of HIV infection in the decade of the 1980s will result in an epidemic of AIDS in the 1990s, which will place great social and economic strains on many countries, particularly those in many areas of the developing world.

Strategies for laboratory HIV testing: an examination of alternative approaches not requiring Western blot.

Advances in laboratory tests for antibodies to human immunodeficiency virus (HIV) have permitted the development of alternative HIV testing strategies that do not require use of the Western blot approach. Three strategies are proposed. In strategy I, sera are tested for HIV antibody using an enzyme-linked immunosorbent assay (ELISA)/rapid/simple (ERS) test; in strategy II, sera reactive in an initial ERS test are retested using a second ERS test; strategy III involves retesting with a third ERS test all sera reactive in two previous ERS tests. Where the objective is identification of asymptomatic HIV-infected individuals, strategy III is proposed where HIV prevalences in the study population are < or = 10%, and strategy II at prevalences > 10%. Strategy II is recommended where the diagnosis of HIV-related disease requires HIV testing. For serosurveillance, strategy II is recommended if the prevalence is < or = 10%, and strategy I if the prevalences are > 10%. Use of strategy I is recommended for transfusion and transplantation safety, at any prevalence. Lower-cost laboratory HIV testing will permit such testing to become more widely available.

PIP: Testing of sera for antibodies to HIV typically involves screening with enzyme-linked immunosorbent assays (ELISA) and subsequent confirmation with Western blot (WB). Western blot testing, however, is relatively expensive and technically demanding. Recent technological advances have produced tests which provide results equivalent in accuracy to those obtained by WB. These include new ELISA tests, simple tests, and rapid tests. Simple tests are those which are easily learned and require no additional equipment or instrumentation, while rapid tests yield results in 30 minutes or less. The lower cost of these methods will allow HIV testing to become more widely available. The authors propose alternative laboratory HIV testing strategies based upon these newer ELISA/rapid/simple tests (ERS). Strategy 1 tests sera for HIV antibody using ERS tests. Strategy 2 retests sera reactive to initial ERS, and strategy 3 simply retests reactive sera a third time with ERS tests. Strategy 1 is recommended for transfusion and transplantation safety at any prevalence of HIV infection is selected populations. Strategy 1 is also recommended for serosurveillance in study populations where the prevalence of HIV infection is greater than 10%, but strategy 2 is recommend where prevalence are less than or equal to 10%. Strategy 2 is generally recommended when diagnosis of HIV-related disease requires HIV testing. Finally, strategy 3 is proposed to identify asymptomatic HIV-infected individuals where HIV prevalence in the study population are less than or equal to 10%, but strategy 2 will suffice where prevalence are greater than 10%.

Reducing the cost of HIV antibody testing.

Available tests to detect antibody to human immunodeficiency virus (HIV) have a range of applications, and injudicious selection and inappropriate use can add a significant financial burden to budgets for AIDS programmes in developing countries. There are several ways by which the cost of HIV antibody testing can be reduced; they include use of tests appropriate for existing laboratory capabilities; adoption of cost-effective testing strategies; pooling of serum samples before testing; and ensuring best possible purchase prices. Each approach can significantly reduce the cost of HIV antibody testing alone or in combination, which increases the potential sustainability of antibody testing programmes, even in settings of limited resources.

PIP: The cost-saving strategies of HIV antibody testing are assessed. The enzyme-linked immunosorbent assay (ELISA) is deemed the most efficient and reliable test for processing 100 samples/day in a large blood bank. Up to 82% can be saved if the western blot is replaced by a suitable ELISA or rapid or simple test. WHO has recommended testing for HIV antibody that uses ELISA with or without rapid and simple assays in place of the ELISA plus western blot strategy. The testing strategies recommended are as follows: 1) All serum is tested with one ELISA or a rapid or simple assay. Reactive samples are taken to be positive for HIV antibody and non-reactive samples to be HIV-antibody negative; 2) All serum is first tested as in strategy 1, and any sample reactive in the first assay is retested with a second ELISA or rapid/simple assay based on a different antigen preparation, a different test principle (indirect vs. competitive), or both; 3) All serum is first tested as in strategy 1, and any reactive samples are retested with a different assay. Strategy 3 requires a third test if the serum is reactive in the first and second assays. Screening for HIV antibody in pooled serum from up to 5 individuals can also reduce the cost. Pooling methods assessed in blood banking systems in Zaire, Zimbabwe, Ecuador, the Philippines, and the Caribbean proved to be as sensitive and specific as individual sample testing. The use of strategy 1 to test only pooled serum saves about 75%, and testing of pooled serum with subsequent identification of affected seropositive individuals saves about 55%. WHO recommends a maximum pool of 5 samples for areas with seroprevalence of 2%. The simple particle agglutination method on the pooled serum can also save costs. Test kits cost from $1.20 per test for ELISA to more than $30 for western blot. In 1990, the Global Program on AIDS bought HIV diagnostic test kits; a saving to countries of about 44% will be achieved through the bulk purchase of tests from kit manufactures.

Cisplatin inhibits in vitro translation by preventing the formation of complete initiation complex.

We previously reported that mRNA loses the ability to direct in vitro peptide synthesis after incubation with cisplatin. The present study was designed to determine the step in translation that is affected. The rates of translation reactions inhibited by cisplatin were biphasic, having an initial rate comparable to that of the uninhibited reaction before decreasing. Analysis of cisplatin-inhibited reactions in sucrose density gradients showed a decrease in polyribosome formation. These results are consistent with an inhibition of the initiation step of protein synthesis. Individual steps in initiation were tested by analyzing the formation of ribosomal subunits in sucrose gradients that resolve the incomplete complexes. Cisplatin caused an accumulation of 48 S particles accompanied by a decreased amount of completed 80 S initiation complexes. Similar results were obtained in experiments utilizing radiolabeled methionine or mRNA. We conclude that cisplatin blocks the initiation of translation by preventing the joining of the 60 S ribosomal subunit to the 48 S preinitiation subunit.

Successful management of paraprotein-associated peripheral polyneuropathies by immunoadsorption of plasma with staphylococcal protein A.

Two patients with paraprotein-associated peripheral polyneuropathy were treated successfully using immunoadsorption of patient's plasma with staphylococcal protein A. Both had previously been treated with immunosuppressive agents or plasma exchange, and were rapidly relapsing at the time of their protein A immunoadsorption therapy. One patient was treated "on-line" with a blood cell separator, and one was treated "off-line." Both responded well to therapy with minimal toxicity. Serum levels of circulating immune complexes were elevated in one patient and remained so during and after therapy. Immunoadsorption with protein A should be investigated as a therapeutic option for patients with paraprotein-associated peripheral polyneuropathy. The therapy is relatively easy to administer, particularly "off-line," and was well tolerated by our patients. More experience, including formal clinical trials, will be required to properly define the indications for, and mechanism of response to, this therapy.

Evaluating national AIDS programmes: new core indicators.

PIP: National AIDS Programs (NAPs) need assistance in evaluating the implementation, relevance, and adequacy of programs. This article distills important features of reviews of NAPs which can form the basis of reprogramming. These features included management information, prevention indicators, condom availability, sexually transmitted disease (STD) case management, evaluation outcomes, HIV/syphilis prevalence, and recommended program indicators and evaluation protocols. It is expected that in January 1994 a WHO evaluation package will be available for WHO regional offices and NAPs, and regional training workshops for NAP staff will follow. WHO's Global Programme on AIDS (GPA) is developing a microcomputer spreadsheet with database functions for extracting, sorting, and searching for data and insertion of textual information. Reports may then be generated for planning, monitoring, coordinating, and reporting to program staff and donors. The prevention indicators (PIs) developed by GPA include knowledge of prevention practices, condom availability, sexual behavior change, quality of STD case management, and HIV/STD seroprevalence. Age and sex statistics will be extracted from community surveys, health facility surveys, serosurveys in prenatal clinics, and reviews of condom distribution records. The PIs were developed only for intra-country comparisons and were field-tested in 1992-93 in 8 countries. The condom measures included the average number of condoms available per person aged 15-49 years annually and estimates of the stock of condoms on hand at the beginning of the previous 12-month period. Methods of data collection for condom indicators was provided. STD data collection involves enumeration of health care facilities and case management with STD care and individual health care provider practices. Protocols provide for appropriate STD assessment and treatment and advice to be given on condoms and partner notification. Repeated interview population surveys are designed to measure condom usage and reported number of sexual partners, symptoms of urethritis in adult men, and knowledge of prevention practices in urban and rural areas.^ieng

Tirilazad mesylate protects vitamins C and E in brain ischemia-reperfusion injury.

Brain concentrations of the antioxidant vitamins C and E decreased following unilateral carotid occlusion and reperfusion for 2 or 24 h in gerbils. Administration of the 21-aminosteroid inhibitor of lipid peroxidation, tirilazad mesylate (U74006F), prevented the decrease in level of both of these vitamins following 2 h of reperfusion. After 24 h of reperfusion, however, alpha-tocopherol (vitamin E) continued to be protected, but ascorbic acid (vitamin C) showed a pronounced decrease in content. The changes in concentrations of these vitamins are consistent with U74006F acting to inhibit peroxidation in the CNS by scavenging of lipid peroxyl radicals and suggest that, in the presence of this agent, injury-induced depletion of ascorbic acid may occur without irreversible tissue damage.

The present and future course of the AIDS epidemic in Côte d'Ivoire.

An assessment of the current and future mortality and morbidity from acquired immunodeficiency syndrome (AIDS) in Côte d'Ivoire was made using the results of the 1989 national survey of the prevalence of human immunodeficiency (HIV) infection in the country and the AIDS projection model developed by WHO. For 1989 it was estimated that about 25,000 AIDS cases in adults and children had occurred, although the total number of cases reported for 1989 (up to 1 July 1991) was about 13% (1:6.9) of this estimated total. It is projected that by 1994 in Côte d'Ivoire the cumulative number of cases of AIDS in adults will be 89,000, and that for infants and children the corresponding number will be 41,000. It was also projected that about 371,000 uninfected children will have been born to HIV-infected mothers in Côte d'Ivoire by 1994 and that many of these children will have been orphaned by the deaths of their mothers from AIDS.