Treatment of Herpes Zoster

Resolution of acute pain related to herpes zoster is accelerated with any of the following: oral acyclovir (Zovirax) 800 mg five times daily for seven days; valacyclovir (Valtrex) 1,000 mg three times daily for seven days; or famciclovir (Famvir) 750 mg once daily, 500 mg twice daily, or 250 mg three times daily for seven days. (Strength of recommendation: A) Oral corticosteroids given during the acute phase of the illness have not been shown to reduce the incidence or severity of postherpetic neuralgia. (Strength of recommendation: B) There is no evidence to support the use of tricyclic antidepressants or anticonvulsants for the management of herpes zoster. (Strength of recommendation: B

Prolonged-acting, multi-targeting gallium nanoparticles potently inhibit growth of both HIV and mycobacteria in co-infected human macrophages.

Human immunodeficiency virus (HIV) infection and Mycobacterium tuberculosis (TB) are responsible for two of the major global human infectious diseases that result in significant morbidity, mortality and socioeconomic impact. Furthermore, severity and disease prevention of both infections is enhanced by co-infection. Parallel limitations also exist in access to effective drug therapy and the emergence of resistance. Furthermore, drug-drug interactions have proven problematic during treatment of co-incident HIV and TB infections. Thus, improvements in drug access and simplified treatment regimens are needed immediately. One of the key host cells infected by both HIV and TB is the mononuclear phagocyte (MP; monocyte, macrophage and dendritic cell). Therefore, we hypothesized that one way this can be achieved is through drug-targeting by a nanoformulated drug that ideally would be active against both HIV and TB. Accordingly, we validated macrophage targeted long acting (sustained drug release) gallium (Ga) nanoformulation against HIV-mycobacterium co-infection. The multi-targeted Ga nanoparticle agent inhibited growth of both HIV and TB in the macrophage. The Ga nanoparticles reduced the growth of mycobacterium and HIV for up to 15 days following single drug loading. These results provide a potential new approach to treat HIV-TB co-infection that could eventually lead to improved clinical outcomes

Should we identify and treat hyperlipidemia in the advanced elderly?

No randomized controlled trials exist that identify and treat hyperlipidemia for advanced elderly patients (age >80 years). Expert and consensus guidelines state that hyperlipidemia found in any patient with coronary artery disease (CAD), or at risk of CAD, should be treated irrespective of age; however, evidence is limited to support lowering lipids for advanced elderly patients with and without known CAD (strength of recommendation: C, based on expert and consensus guidelines)

Gallium nanoparticles facilitate phagosome maturation and inhibit growth of virulent Mycobacterium tuberculosis in macrophages.

New treatments and novel drugs are required to counter the growing problem of drug-resistant strains of Mycobacterium tuberculosis (M.tb). Our approach against drug resistant M.tb, as well as other intracellular pathogens, is by targeted drug delivery using nanoformulations of drugs already in use, as well as drugs in development. Among the latter are gallium (III) (Ga)-based compounds. In the current work, six different types of Ga and rifampin nanoparticles were prepared in such a way as to enhance targeting of M.tb infected-macrophages. They were then tested for their ability to inhibit growth of a fully pathogenic strain (H37Rv) or a non-pathogenic strain (H37Ra) of M.tb. Encapsulating Ga in folate- or mannose-conjugated block copolymers provided sustained Ga release for 15 days and significantly inhibited M.tb growth in human monocyte-derived macrophages. Nanoformulations with dendrimers encapsulating Ga or rifampin also showed promising anti-tuberculous activity. The nanoparticles co-localized with M.tb containing phagosomes, as measured by detection of mature cathepsin D (34 kDa, lysosomal hydrogenase). They also promoted maturation of the phagosome, which would be expected to increase macrophage-mediated killing of the organism. Delivery of Ga or rifampin in the form of nanoparticles to macrophages offers a promising approach for the development of new therapeutic anti-tuberculous drugs

Effects of human serum on bacterial competition with neutrophils for molecular oxygen.

A dialyzable factor(s) in human serum is known to stimulate gonococcal oxygen consumption. Its effect on other human pathogens was investigated. A 10% serum solution increased peak O2 consumption for Escherichia coli and Staphylococcus aureus to 157% (P less than 0.05) and 199% (P less than 0.02), respectively, of their O2 consumption when suspended in Hanks balanced salt solution, compared with a 356% increase for Neisseria gonorrhoeae with serum. Dialyzed serum lacked stimulatory capacity. Bacteria, serum, and neutrophils are often incubated to evaluate neutrophil bactericidal activity. Samples of 10(8) N. gonorrhoeae, S. aureus, and E. coli turned resazurin colorless (anaerobic conditions, Eh less than -42 mV) after 7.4, 13.3, and 15.1 min, respectively. Because neutrophil formation of reactive oxygen intermediates requires ambient O2, the effect of live bacteria and serum on this process was explored. After 5 min of incubation of 10(8) N. gonorrhoeae or S. aureus in 10% normal or dialyzed serum, 10(5) neutrophils were added. Phorbol myristate acetate was then added to assure neutrophil stimulation, and luminol-dependent luminescence was measured. N. gonorrhoeae and S. aureus incubation in normal serum decreased peak LDL 91.7 and 88.6%, respectively, relative to incubation in dialyzed serum. A sample of 10(8) E. coli totally eliminated LDL. A sample of 10(8) E. coli incubated in Hanks balanced salt solution for 5 min also eliminated phorbol myristate acetate induced neutrophil H2O2 production. LDL inhibition increased in proportion to bacterial concentration and time of incubation and was prevented by inclusion of KCN. Increasing the concentration of neutrophils to 10(8) (1:1 particle-to-cell ratio) only partially reversed LDL inhibition. Re-aeration of the system allowed brief LDL which persisted only if KCN was added. Addition of KCN after bacterial incubation also permitted LDL, arguing against depletion of other factors from the media or accumulation of bacterially derived inhibitory substances. A dynamic competition for O2 occurs between bacteria and neutrophils. Serum stimulation of bacterial O2 utilization may contribute to virulence by increasing bacterial capacity to inhibit neutrophil function

Do human neutrophils make hydroxyl radical? Detection of free radicals by human neutrophils activated with a soluble or particulate stimulus using electron paramagnetic resonance spectrometry

Using electron paramagnetic resonance spectrometry and the spin trap 5,5-dimethyl-1-oxide (DMPO), neutrophil free radical production in response to phorbol myristate acetate and opsonized zymosan was investigated. Using phorbol myristate acetate and zymosan (3 mg/ml), the superoxide spin-trapped adduct 2-2-dimethyl-5-hydroperoxy-1-pyrrolidinyloxyl (DMPO-OOH) and the hydroxyl spin-trapped adduct 2-2-dimethyl-5-hydroxy-1-pyrrolidinyloxyl (DMPO-OH) were detected. Only DMPO-OH was observed with zymosan (0.5 mg/ml). Hydroxyl radical production in the presence of dimethylsulfoxide (Me2SO) and DMPO yields 2,2,5-trimethyl-1-pyrrolidinyloxyl. The only 2,2-trimethyl-1-pyrrolidinyloxyl detected following neutrophil stimulation was that expected from DMPO-OOH degradation. Superoxide dismutase but not catalase inhibited generation of all three spin-trapped adducts. These data indicate that DMPO-OH arose from DMPO-OOH degradation and does not represent hydroxyl radical production. Under certain conditions DMPO-OH is the predominant spin-trapped adduct resulting from neutrophil superoxide production, perhaps due to cellular bioreduction of DMPO-OOH to DMPO-OH. Cytochalasin B, which prevents phagosome closure, inhibited zymosan-stimulated neutrophil oxygen consumption and electron paramagnetic resonance superoxide detection. No hydroxyl radical was detected. Spin trapping with DMPO appears to detect intraphagosomal free-radical formation

A systematic review of universal, teacher-led interventions targeting anxiety in U.S. schools

Implications of anxiety symptomatology experienced among children and adolescents in the US constitute a major public health crisis, calling for promising universal mental health interventions in K-12 schools. Schools represent an ideal setting for the implementation of population based, public health interventions, as children and adolescents spend a significant proportion of time in school. Discussions within the scientific community document several advantages to utilization of universal, Tier1 interventions. However, the efficacy of universal, school-based anxiety interventions in the US are not consistently documented. The purpose of this study is to systematically review the literature to identify the efficacy of universal teacher-led school-based anxiety interventions in the US. A comprehensive literature search was conducted employing PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, PsycINFO, Education Resources Information Center (ERIC), and Google Scholar databases up to December 2016. Each of the articles was independently reviewed for relevance and inclusionary criteria, with five studies meeting these criteria. Overall, the quality of the included studies was moderate. All reviewed studies found that universal teacher-led anxiety interventions in school-based programs had a positive impact on the anxiety outcomes of students when compared to control groups. However, several methodological and design concerns were identified across studies. While our findings suggest that universal teacher-led anxiety interventions have the potential to reduce anxiety symptomatology among school-aged children in the US, further research is needed.https://digitalcommons.unmc.edu/coph_pres/1009/thumbnail.jp

Effects of human serum on the growth and metabolism of Neisseria gonorrhoeae: an alternative view of serum.

Humans are the sole reservoir of Neisseria gonorrhoeae, an organism which undergoes a marked increase in metabolic rate after exposure to a low-molecular-weight, heat-stable component(s) of human serum. Further studies on the effect of serum on gonococcal metabolism were undertaken. Gonococcal broth (GCB) is commonly used for in vitro cultivation of gonococci. Gonococci suspended in GCB plus 10% serum exhibited oxygen consumption rates of 139% (P less than 0.01) and 456% (P less than 0.01) of those suspended in GCB or Hanks balanced salt solution, respectively. A twofold increase in growth rate also resulted from the addition of 10% serum to GCB. Gonococcal 14C-labeled adenine incorporation increased threefold with 10% serum supplementation of Hanks balanced salt solution. Dialysis of serum in 1,000-molecular-weight exclusion tubing removed the stimulatory factor(s). Neither correction of anion-cation concentrations altered by dialysis nor addition of substances of known importance to the metabolism of gonococci (i.e., lactate, pyruvate, cysteine, ATP, AMP, NADPH, amino acids, malate, and glutathione) to dialyzed serum reconstituted stimulatory capacity. The effect of serum on gonococcal glucose-catabolic pathways was measured by modified radiospirometry. An apparent threefold increase in Entner-Doudoroff and pentose phosphate pathway activities was induced by 10% serum, as was the increased shunting of glucose-derived glyceraldehyde-3-phosphate into these pathways. These metabolic changes did not allow specific identification of the serum stimulatory factor(s). Acetate, the major by-product of gonococcal glucose catabolism, inhibited gonococcal oxygen consumption as previously reported. A high-molecular-weight serum component, probably albumin, reversed acetate-mediated inhibition of gonococcal oxygen consumption, identifying a second mechanism by which serum increases gonococcal metabolism. These results suggest that supplementation of growth media with serum should be considered to provide N. gonorrhoeae with conditions more consistent with its normal environment

Spin-trapping and Human Neutrophils: Limits of detection of hydroxyl radical

Using the spin trap, 5,5-dimethyl-1-pyrroline-1-oxide (DMPO) and an excess of dimethyl sulfoxide, we previously reported that in the absence of an exogenous iron catalyst, human neutrophils will not generate hydroxyl radical, manifested as the catalyse-inhibitable methyl radical spin-trapped adduct, 2,2,5-trimethyl-1-pyrrolidinyloxy (DMPO-CH3) (Britigan, B.E., Rosen, G.M., Chai, Y., and Cohen, M.S. (1986) J. Biol. Chem. 261, 4426-4431). However, superoxide destroys the preformed hydroxyl radical spin-trapped adduct, 2,2-dimethyl-5-hydroxy-1-pyrrolidinyloxy (DMPO-OH), and DMPO-CH3. The present study was undertaken to better resolve the limits of sensitivity of the spin-trapping method. Photolytically generated DMPO-CH3 and DMPO-OH slowly decomposed in the presence of a low flux (1 μM/min) of enzymatically (xanthine/xanthine oxidase)-generated superoxide, but more rapid decomposition of these adducts occurred with higher superoxide flux (5 μM/min). Inclusion of cysteine markedly increased the rate of DMPO-OH and DMPO-CH3 decomposition, masking the effects of superoxide alone. The addition of varying concentrations of superoxide dismutase did not lead to increased formation of DMPO-OH or DMPO-CH3, as should have occurred if these adducts were being destroyed by superoxide. As a positive control, we employed an iron-supplemented system with phorbol 12-myristate 13-acetate-stimulated neutrophils or xanthine/xanthine oxidase to generate DMPO-CH3. Addition of superoxide dismutase increased the magnitude of DMPO-CH3, primarily by increasing the rate of hydrogen peroxide formation, and to a lesser extent by prolonging the half-life of DMPO-CH3. Although spin-trapped adducts can be destroyed by a high concentration of superoxide, or by lower concentrations of superoxide in the presence of thiol-containing compounds, our results demonstrate that such decomposition does not interfere with the ability of the spin-trapping method to detect hydroxyl radical generated by human neutrophils. These data do not support the capacity of neutrophils to generate hydroxyl radical in the absence of an exogenous Haber-Weiss catalyst