Despite the growing worldwide burden of dengue fever, the global economic impact of dengue illness is poorly documented. Using a common protocol, we present the first multicountry estimates of the direct and indirect costs of dengue cases in eight American and Asian countries. We conducted prospective studies of the cost of dengue in five countries in the Americas (Brazil, El Salvador, Guatemala, Panama, and Venezuela) and three countries in Asia (Cambodia, Malaysia, and Thailand). All studies followed the same core protocol with interviews and medical record reviews. The study populations were patients treated in ambulatory and hospital settings with a clinical diagnosis of dengue. Most studies were performed in 2005. Costs are in 2005 international dollars (I$). We studied 1,695 patients (48% pediatric and 52% adult); none died. The average illness lasted 11.9 days for ambulatory patients and 11.0 days for hospitalized patients. Among hospitalized patients, students lost 5.6 days of school, whereas those working lost 9.9 work days per average dengue episode. Overall mean costs were I$514 and I$1,394 for an ambulatory and hospitalized case, respectively. With an annual average of 574,000 cases reported, the aggregate annual economic cost of dengue for the eight study countries is at least I$587 million. Preliminary adjustment for under-reporting could raise this total to $1.8 billion, and incorporating costs of dengue surveillance and vector control would raise the amount further. Dengue imposes substantial costs on both the health sector and the overall economy.

The rates of whole body nitric oxide (NO) synthesis, plasma arginine flux, and de novo arginine synthesis and their relationships to urea production, were examined in a total of seven healthy adults receiving an L-amino acid diet for 6 days. NO synthesis was estimated by the rate of conversion of the ['5N] indicating that -11% of the plasma arginine flux originates via conversion of plasma citrulline to arginine. Thus, the fraction of the plasma arginine flux associated with NO and also urea synthesis in healthy humans is small, although the plasma arginine compartment serves as a significant precursor pool (54%) for whole body NO formation. This tracer model should be useful for exploring these metabolic relationships in vivo, under specific pathophysiologic states where the L-arginine-NO pathway might be altered.Arginine serves various important metabolic functions, including roles in protein synthesis, nitrogen transport and elimination (1, 2), and as the precursor of nitric oxide (NO), which is a current area of considerable research interest (3-5). Oxidation of arginine by a homodimeric group of nitric oxide synthases yields citrulline and nitric oxide in stoichiometric amounts, with each containing a nitrogen atom derived from the guanidino moiety of arginine. NO undergoes oxidative degradation to the stable end products nitrite (NO-) and nitrate (NO-). In the in vivo system, NO-is readily oxidized to NO{ via hemoglobin, and so NO is eventually detected in plasma or urine as NOK (5) and its measurement has been used to estimate the rate of whole body NO synthesis.It has been suggested that therapeutic modulation of nitric oxide production may be achieved by supplying the precursor arginine (6-9) or by inhibiting NO production with L-arginine analogs (10-12). However, before profound changes in exogenous arginine intake levels or a pharmacologic inhibition of NO formation can be safely recommended, it is desirable to gain a better understanding of the regulation of whole body arginine metabolism in human subjects and its quantitative interrelationships with the L-arginine-NO pathway.In our previous studies, using stable isotopic tracer techniques, we have investigated whole body arginine metabolism and the use of arginine for NO synthesis, by measurement of the transfer of the guanidino nitrogen of plasma arginine to urinary NO-. These studies have been carried out in healthy humans receiving variable levels of arginine intake (13-15), and in infants with pulmonary hypertension (16). We have now extended these earlier investigations of whole body arginine homeostasis and the metabolism of urea cycle intermediates by examining the kinetics of arginine metabolism throughout a continuous 24-35-hr period. Using this design, it has been possible, for the first time to our knowledge, to determine the in vivo rate of conversion of [15N]guanidino arginine to [15N]ureido citrulline and NO, presumably due to the NO synthase reaction. We compared this estimate with the rate of transfer of the guanidino nitroge...

In an effort to attain earlier diagnoses in children with hemophagocytic lymphohistiocytosis (HLH), the International Histiocyte Society has now broadened their diagnostic criteria to no longer differentiate primary (HLH) and secondary hemophagocytic lymphohistiocytosis (SHLH). Five of the following eight diagnostic criteria needed to be met: 1) fever, 2) cytopenia of two lines, 3) hypertriglyceridemia and/or hypofibrinogenemia, 4) hyperferritinemia (>500 microg/L), 5) hemophagocytosis, 6) elevated soluble interleukin-2 receptor (CD25), 7) decreased natural killer-cell activity, and 8) splenomegaly can also commonly be found in patients with sepsis, systemic inflammatory response syndrome (SIRS), multiorgan dysfunction syndrome (MODS), and macrophage activation syndrome (MAS). Nevertheless, the therapeutic options for these are radically different. Chemotherapy and bone marrow transplant have been used for treatment of HLH/SHLH, whereas antibiotics and supportive treatment are used in severe sepsis/SIRS and MODS. MAS is treated with limited immune suppression. Outcomes are also different, SHLH has a mortality rate around 50%, whereas pediatric septic shock and MODS have a mortality of 10.3% and 18%, respectively, and severe sepsis in previously healthy children has a mortality rate of 2%. MAS has a mortality rate between 8% and 22%. Because SHLH and severe sepsis/SIRS/MODS/MAS share clinical and laboratory inflammatory phenotypes, we recommend extreme caution when considering applying HLH therapies to children with sepsis/SIRS/MODS/MAS. HLH therapies are clearly warranted for children with HLH; however, a quantitative functional estimate of cytotoxic lymphocyte function may be a more precise approach to define the overlap of these conditions, better identify these processes, and develop novel therapeutic protocols that may lead to improved treatments and outcomes.

IntroductionLiterature on influenza focuses on influenza A, despite influenza B having a large public health impact. The Global Influenza B Study aims to collect information on global epidemiology and burden of disease of influenza B since 2000.MethodsTwenty-six countries in the Southern (n = 5) and Northern (n = 7) hemispheres and intertropical belt (n = 14) provided virological and epidemiological data. We calculated the proportion of influenza cases due to type B and Victoria and Yamagata lineages in each country and season; tested the correlation between proportion of influenza B and maximum weekly influenza-like illness (ILI) rate during the same season; determined the frequency of vaccine mismatches; and described the age distribution of cases by virus type.ResultsThe database included 935 673 influenza cases (2000–2013). Overall median proportion of influenza B was 22·6%, with no statistically significant differences across seasons. During seasons where influenza B was dominant or co-circulated (>20% of total detections), Victoria and Yamagata lineages predominated during 64% and 36% of seasons, respectively, and a vaccine mismatch was observed in ≈25% of seasons. Proportion of influenza B was inversely correlated with maximum ILI rate in the same season in the Northern and (with borderline significance) Southern hemispheres. Patients infected with influenza B were usually younger (5–17 years) than patients infected with influenza A.ConclusionInfluenza B is a common disease with some epidemiological differences from influenza A. This should be considered when optimizing control/prevention strategies in different regions and reducing the global burden of disease due to influenza.

The fluxes of arginine and citruiline through plasma and the rate of conversion of labeled citrulline to arginine were estimated in two pilot studies (with a total of six adult subjects) and in a dietary study with five healthy young men. These latter subjects received an L-amino acid-based diet that was arginine-rich or arginine-free each for 6 days prior to conduct, on day 7, of an 8-hr (first 3 hr, fast; final 5 hr, fed) primed continuous intravenous infusion protocol using L- [guandno-93C]arginine, L-[5,5-2H2]citrulline, and L- [5,5,5-2H31leucine, as tracers. A pilot study indicated that citrulline flux was about 20% higher (P < 0.05) when determined with [ureido-13C]citrulline compared with [2H2Jcitruline, indicating recycling of the latter tracer. Mean citruilin fluxes were about 8-11 pmol kg'lhr'1 for the various metabolic/diet groups and did not differ significantly between fast and fed states or arginine-rich and arginine-free periods. Arginine fluxes (mean ± SD) were 60.2 ± 5.4 and 73.3 ± 13.9 jAmol kg"l hr'1 for fast and fed states during the arginine-rich period, respectively, and were significantly lowered (P < 0.05), by 20-40%, during the arginine-free period, especially for the fed state, where this was due largely to reduced entry of dietary arginine into plasma. The conversion of plasma citruiline to arginine approximated 5.5 ,umol*kg'l-hr-1 for the various groups and also was unaffected by arginine intake. Thus, endogenous arginine synthesis is not markedly responsive to acute alterations in arginine intake in healthy adults. We propose that argmine homeostasis is achieved largely via modulating arginine intake and/or the net rate of arginine degradation.The physiological needs by tissues and organs for arginine are met via the endogenous synthesis of arginine and/or arginine supplied by the diet. For the U.S. population the latter amounts to about 5.4 g daily per capita (1). The rates of endogenous arginine synthesis in the immature rat (2, 3), guinea pig (4), cat (5, 6), dog (7-9), chicken (10), rabbit (11), and pig (12) of nitric oxide (16) and of creatine and its participation as arginyl-tRNA in the process of ubiquitin-dependent protein degradation (17). Therefore, we have begun to use stableisotope tracer techniques to explore, noninvasively, kinetic and regulatory aspects ofarginine metabolism in adult human subjects (18,19). Here we report results of a study in young men who were given for 7 days an arginine-rich diet and then, for another 7 days, an arginine-free diet. Our kinetic model involves L-[guanidino-13C]arginine and L-[5,5-2H2]citrulline as tracers, to estimate plasma arginine and citrulline fluxes as well as the rate of transfer of plasma citrulline into the arginine pool. From the present findings, and our recent studies (19), we propose an integrative scheme of body arginine homeostasis and balance, which defines the metabolic basis for the conditional indispensability of dietary arginine under various pathophysiological conditions (1, 13, 14). MATERIALS AND METHOD...

The availability of cysteine is thought to be the rate limiting factor for synthesis of the tripeptide glutathione (GSH), based on studies in rodents. GSH status is compromised in various disease states and by certain medications leading to increased morbidity and poor survival. To determine the possible importance of dietary cyst(e)ine availability for whole blood glutathione synthesis in humans, we developed a convenient mass spectrometric method for measurement of the isotopic enrichment of intact GSH and then applied it in a controlled metabolic study. Seven healthy male subjects received during two separate 10-day periods an L-amino acid based diet supplying an adequate amino acid intake or a sulfur amino acid (SAA) (methionine and cysteine) free mixture (SAA-free). On day 10, L-[1-13 C]cysteine was given as a primed, constant i.v. infusion (3mol⅐kg ؊1 ⅐h ؊1 ) for 6 h, and incorporation of label into whole blood GSH determined by GC͞MS selected ion monitoring. The fractional synthesis rate (mean ؎ SD; day -1 ) of whole blood GSH was 0.65 ؎ 0.13 for the adequate diet and 0.49 ؎ 0.13 for the SAA-free diet (P < 0.01). Whole blood GSH was 1,142 ؎ 243 and 1,216 ؎ 162 M for the adequate and SAA-free periods (P > 0.05), and the absolute rate of GSH synthesis was 747 ؎ 216 and 579 ؎ 135 mol⅐liter ؊1 ⅐day ؊1 , respectively (P < 0.05). Thus, a restricted dietary supply of SAA slows the rate of whole blood GSH synthesis and diminishes turnover, with maintenance of the GSH concentration in healthy subjects.

Arginine has vasodilatory effects, via its conversion by NO synthase into NO, and immunomodulatory actions which play important roles in sepsis. Protein breakdown affects arginine availability and the release of asymmetric dimethylarginine, an inhibitor of NO synthase, may therefore affect NO synthesis in patients with sepsis. The objective of the present study was to investigate whole-body in vivo arginine and citrulline metabolism and NO synthesis rates, and their relationship to protein breakdown in patients with sepsis or septic shock and in healthy volunteers. Endogenous leucine flux, an index of whole-body protein breakdown rate, was measured in 13 critically ill patients with sepsis or septic shock and seven healthy controls using an intravenous infusion of [1-13C]leucine. Arginine flux, citrulline flux and the rate of conversion of arginine into citrulline (an index of NO synthesis) were measured with intravenous infusions of [15N2]guanidino-arginine and [5,5-2H2]citrulline. Plasma concentrations of nitrite plus nitrate, arginine, citrulline and asymmetric dimethylarginine were measured. Compared with controls, patients had a higher leucine flux and higher NO metabolites, but arginine flux, plasma asymmetric dimethylarginine concentration and the rate of NO synthesis were not different. Citrulline flux and plasma arginine and citrulline were lower in patients than in controls. Arginine production was positively correlated with the protein breakdown rate. Whole-body arginine production and NO synthesis were similar in patients with sepsis and septic shock and healthy controls. Despite increased proteolysis in sepsis, there is a decreased arginine plasma concentration, suggesting inadequate de novo synthesis secondary to decreased citrulline production.

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