Infections and diabetes: Risks and mitigation with reference to India.

BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes.

Trait-specific effects of exogenous triiodothyronine on cytokine and behavioral responses to simulated systemic infection in male Siberian hamsters.

Seasonal changes in day length enhance and suppress immune function in a trait-specific manner. In Siberian hamsters (Phodopus sungorus) winter-like short days (SDs) increase blood leukocyte concentrations and adaptive T cell dependent immune responses, but attenuate innate inflammatory responses to simulated infections. Thyroid hormone (TH) signaling also changes seasonally and has been implicated in modulation of the reproductive axis by day length. Immunologically, TH administration in long days (LD) enhances adaptive immune responses in male Siberian hamsters, mimicking effects of SDs. This experiment tested the hypothesis that T3 is also sufficient to mimic the effects of SD on innate immune responses. Adult male hamsters housed in LDs were pretreated with triiodothyronine (T3; 1 µg, s.c.) or saline (VEH) daily for 6 weeks; additional positive controls were housed in SD and received VEH, after which cytokine, behavioral, and physiological responses to simulated bacterial infection (lipopolysaccharide; LPS) were evaluated. SD pretreatment inhibited proinflammatory cytokine mRNA expression (i.e. interleukin 1ß, nuclear factor kappa-light-chain-enhancer of activated B cells). In addition, the magnitude and persistence of anorexic and cachectic responses to LPS were also lower in SD hamsters, and LPS-induced inhibition of nest building behavior was absent in SD. T3 treatments failed to affect behavioral (food intake, nest building) or somatic (body mass) responses to LPS in LD hamsters, but one CNS cytokine response to LPS (e.g., hypothalamic TNFα) was augmented by T3. Together these data implicate thyroid hormone signaling in select aspects of innate immune responses to seasonal changes in day length.

Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors.

The acute inflammatory response is host-protective to contain foreign invaders. Many of today's pharmacopeia that block pro-inflammatory chemical mediators can cause serious unwanted side effects such as immune suppression. Uncontrolled inflammation is now considered a pathophysiologic basis associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity and asthma, as well as the classic inflammatory diseases, e.g. arthritis, periodontal diseases. The inflammatory response is designated to be a self-limited process that produces a superfamily of chemical mediators that stimulate resolution of inflammatory responses. Specialized proresolving mediators (SPM) uncovered in recent years are endogenous mediators that include omega-3-derived families resolvins, protectins and maresins, as well as arachidonic acid-derived (n-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, reduce pain and promote tissue regeneration via novel mechanisms. Here, we review recent evidence from human and preclinical animal studies, together with the structural and functional elucidation of SPM indicating the SPM as physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. These results suggest that it is time to develop immunoresolvents as agonists for testing resolution pharmacology in nutrition and health as well as in human diseases and during surgery.

Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Practitioners of ancient societies from the time of Hippocrates and earlier recognized and treated the signs of inflammation, heat, redness, swelling, and pain with agents that block or inhibit proinflammatory chemical mediators. More selective drugs are available today, but this therapeutic concept has not changed. Because the acute inflammatory response is host protective to contain foreign invaders, much of today's pharmacopeia can cause serious unwanted side effects, such as immune suppression. Uncontrolled inflammation is now considered pathophysiologic and is associated with many widely occurring diseases such as cardiovascular disease, neurodegenerative diseases, diabetes, obesity, and asthma, as well as classic inflammatory diseases (e.g., arthritis and periodontal diseases). The inflammatory response, when self-limited, produces a superfamily of chemical mediators that stimulate resolution of the response. Specialized proresolving mediators (SPMs), identified in recent years, are endogenous mediators that include the n-3-derived families resolvins, protectins, and maresins, as well as arachidonic acid-derived (n-6) lipoxins, which promote resolution of inflammation, clearance of microbes, reduction of pain, and promotion of tissue regeneration via novel mechanisms. Aspirin and statins have a positive impact on these resolution pathways, producing epimeric forms of specific SPMs, whereas other drugs can disrupt timely resolution. In this article, evidence from recent human and preclinical animal studies is reviewed, indicating that SPMs are physiologic mediators and pharmacologic agonists that stimulate resolution of inflammation and infection. The findings suggest that it is time to challenge current treatment practices-namely, using inhibitors and antagonists alone-and to develop immunoresolvents as agonists to test resolution pharmacology and their role in catabasis for their therapeutic potential.-Serhan, C. N. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms.

Evaluation of the medicinal properties of Cyrtocarpa procera Kunth fruit extracts.

BACKGROUND: The fruit of Cyrtocarpa procera is used to treat stomach diseases by people living in San Rafael, Coxcatlan, Puebla. This work investigated the antibacterial, antioxidant, cytotoxic and anti-inflammatory activities of the fruit produced by this species. METHODS: Methanol extract was obtained by maceration. After obtaining the methanol extract (MeOH1), methanol subextract (MeOH2) and hexane (H) were obtained. The antibacterial activities of MeOH1, MeOH2 and H were evaluated through disc-diffusion. The quenching of free radicals was evaluated by decolorizing a methanolic DPPH solution. The cytotoxic activity of MeOH2 was evaluated by in vitro assay system of growth inhibition of human cervical carcinoma cell line (CasKi). The IL-1ß and TNF-α were determined through ELISA in the supernatants of the macrophage cell line (RAW 264.7). The MeOH2 subextract was separated by column chromatography, seventy-three fractions were collected. RESULTS: The Gram-positive and -negative bacteria examined were sensitive to MeOH1 and MeOH2; the MeOH2 was bactericidal toward Staphyloccocus aureus (MIC = 4 mg/mL) and Vibrio cholera (MIC = 4 mg/mL). The MeOH2 inhibited the DPPH radical (SC50 = 69.7 µg/mL), but a cytotoxicity assay revealed that the extract is not toxic according to the National Cancer Institute (LD50 = 22.03 µg/mL). The production of proinflammatory cytokines (IL- 1ß and TNF- α) by LPS- stimulated macrophages was reduced after the treatments. The methanol extract contained various organic acids, such as citric acid, palmitic acid and α- linoleic acid. CONCLUSIONS: The fruits of Cyrtocarpa procera are employed to treat ailments such as diarrhea, in this study were demonstrated some biological activities involved in a bacterial infection. This is the first research about of the medicinal properties of C. procera fruit.

Infección sistémica por citomegalovirus: influencia del tratamiento con foscarnet en los niveles plasmáticos de calcio y magnesio / Systemic cytomegalovirus infection: Changes in serum calcium and magnesium levels with foscarnet treatment

La infección por citomegalovirus es frecuente en pacientes trasplantados cardiacos. Foscarnet se utiliza, con evidencia limitada, como tratamiento de segunda línea tras el fracaso de ganciclovir en estos pacientes. Presentamos un caso de alteraciones electrolíticas por foscarnet administrado para el tratamiento de infección por citomegalovirus en un paciente pediátrico trasplantado cardiaco. La infección se resolvió tras 6 semanas de tratamiento, apareciendo niveles de calcio iónico bajos durante la infusión del fármaco e hipomagnesemia mantenida tratada con suplementos, que revirtieron al retirar el fármaco

Cytomegalovirus infection is common in cardiac transplant patients. Foscarnet is used, with limited evidence, as second-line treatment after ganciclovir failure in these patients. We describe the case of a paediatric cardiac transplant patient who developed electrolyte disturbances during foscarnet treatment for cytomegalovirus infection. The infection resolved after 6 weeks of treatment. Low ionized calcium and magnesium levels were observed during the drug infusion, which were treated with supplements. The serum levels reverted to normal after drug withdrawal

Pro-resolving lipid mediators are leads for resolution physiology.

Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

Selected terpenoids from medicinal plants modulate endoplasmic reticulum stress in metabolic disorders.

OBJECTIVES: The majority of research performed on cellular stress and apoptosis focuses on mitochondrial dysfunction; however, the importance of the endoplasmic reticulum dysfunction and the link to metabolic diseases has gained a substantial interest. This review focuses on the potential of terpenoids to influence endoplasmic reticulum stress and the possible role terpenoids play as the treatment of metabolic diseases. KEY FINDINGS: Metabolic diseases develop as a result of a cascade of cellular pathways. In most cases, cells are able to compensate for the disruption of the cellular homeostasis although the initiation of response pathways; however, chronic stress initiates apoptotic pathways. This reviewed (1) showed the importance of phytoterpenoids to influence endoplasmic reticulum (ER) stress and homeostasis, (2) showed how regulating ER stress affect the cell survival and death, and (3) highlighted some examples of how the progression of metabolic diseases can be influenced by ER. SUMMARY: Due to the substantial number of terpenoids that have been identified in literature, this review gave examples of 21 terpenoids that have been documented to have an effect on the different proteins associated with ER stress, how these plant terpenoids influence ER dysfunction and metabolic diseases such as diabetes, cancer, liver, and neurological diseases and parasitic infections.

Perspective on fever: the basic science and conventional medicine.

This review describes how fever is generated as a regulated increase in body temperature. It results from an upward shift in the thermoregulatory set point, mediated by pyrogenic cytokines released from monocytes/macrophages in response to infection or trauma. Evidence will be presented that fever is part of an integrated host defense system, and that failure to generate a fever in response to infection is generally associated with a poorer prognosis.

Identification and cloning of a selenophosphate synthetase (SPS) from tiger shrimp, Penaeus monodon, and its transcription in relation to molt stages and following pathogen infection.

Complementary (c)DNA encoding selenophosphate synthetase (SPS) messenger (m)RNA of the tiger shrimp Penaeus monodon, designated PmSPS, was obtained from the hepatopancreas by a reverse-transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE). The 1582-bp cDNA contained an open reading frame (ORF) of 1248 bp, a 103-bp 5'-untranslated region (UTR), and a 231-bp 3'-UTR, which contained a conserved selenocysteine insertion sequence (SECIS) element, a conventional polyadenylation signal, and a poly A tail. The molecular mass of the deduced amino acid (aa) sequence (416 aa) was 45.5 kDa with an estimated pI of 4.85. It contained a putative selenocysteine residue which was encoded by the unusual stop codon, (275)TGA(277), which formed at the active site with residues Sec(58) and Lys(61). A comparison of amino acid sequences showed that PmSPS was more closely related to invertebrate SPS1, such as those of Heliothis virescens and Drosophila melanogaster a and b. PmSPS cDNA was synthesized in all tested tissues, especially in the hepatopancreas. PmSPS in the hepatopancreas of shrimp significantly increased after an injection with either Photobacterium damsela or white spot syndrome virus (WSSV) in order to protect cells against damage from oxidation, and enhance the recycling of selenocysteine or selenium metabolism, indicating that PmSPS is involved in the disease-resistance response. The PmSPS expression by hemocytes significantly increased in stage C, and then gradually decreased until stage A, suggesting that the cloned PmSPS in hemocytes might play a role in viability by renewing hemocytes and antioxidative stress response for new exoskeleton synthesis during the molt cycle of shrimp.

Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection.

Decreased serum thyroid hormone concentrations in severely ill patients were first reported in the 1970s, but the functional meaning of the observed changes in thyroid hormone levels, together known as nonthyroidal illness syndrome (NTIS), remains enigmatic. Although the common view was that NTIS results in overall down-regulation of metabolism in order to save energy, recent work has shown a more complex picture. NTIS comprises marked variation in transcriptional and translational activity of genes involved in thyroid hormone metabolism, ranging from inhibition to activation, dependent on the organ or tissue studied. Illness-induced changes in each of these organs appear to be very different during acute or chronic inflammation, adding an additional level of complexity. Organ- and timing-specific changes in the activity of thyroid hormone deiodinating enzymes (deiodinase types 1, 2, and 3) highlight deiodinases as proactive players in the response to illness, whereas the granulocyte is a novel and potentially important cell type involved in NTIS during bacterial infection. Although acute NTIS can be seen as an adaptive response to support the immune response, NTIS may turn disadvantageous when critical illness enters a chronic phase necessitating prolonged life support. For instance, changes in thyroid hormone metabolism in muscle during critical illness may be relevant for the pathogenesis of myopathy associated with prolonged ventilator dependence. This review focuses on NTIS as a timing-related and organ-specific response to illness, occurring independently from the decrease in serum thyroid hormone levels and potentially relevant for disease progression.

Tryptophan metabolism, from nutrition to potential therapeutic applications.

Tryptophan is an indispensable amino acid that should to be supplied by dietary protein. Apart from its incorporation into body proteins, tryptophan is the precursor for serotonin, an important neuromediator, and for kynurenine, an intermediary metabolite of a complex metabolic pathway ending with niacin, CO(2), and kynurenic and xanthurenic acids. Tryptophan metabolism within different tissues is associated with numerous physiological functions. The liver regulates tryptophan homeostasis through degrading tryptophan in excess. Tryptophan degradation into kynurenine by immune cells plays a crucial role in the regulation of immune response during infections, inflammations and pregnancy. Serotonin is synthesized from tryptophan in the gut and also in the brain, where tryptophan availability is known to influence the sensitivity to mood disorders. In the present review, we discuss the major functions of tryptophan and its role in the regulation of growth, mood, behavior and immune responses with regard to the low availability of this amino acid and the competition between tissues and metabolic pathways for tryptophan utilization.

Bactericidal and anti-inflammatory properties of a standardized Echinacea extract (Echinaforce): dual actions against respiratory bacteria.

Common symptoms of upper respiratory infections, such as sore throat, cough, and inflammation, are often caused by bacteria, sometimes as a complication of virus infection. Extracts of Echinacea purpurea (Asteraceae) have been advocated traditionally for use by individuals suffering from these symptoms, although the underlying basis for the beneficial effects of Echinacea is not known. We hypothesized that Echinacea could inactivate certain respiratory bacteria and could also reverse inflammatory effects caused by these bacteria in epithelial cells. In order to test this we used a commercial standardized extract of Echinacea purpurea (Echinaforce), and a novel cytokine array system designed to measure simultaneously the levels of 20 different cytokines secreted by bronchial epithelial cell cultures in response to infection. Streptococcus pyogenes (Group A Strep), which is often associated with sore throat and more severe pulmonary infections, was readily inactivated by Echinacea, which also completely reversed the cellular pro-inflammatory response. Hemophilus influenzae and Legionella pneumophila were also readily inactivated, and their pro-inflammatory responses reversed. Staphylococcus aureus (methicillin-resistant and sensitive strains) and Mycobacterium smegmatis were less sensitive to the bactericidal effects of Echinacea however, but their pro-inflammatory responses were still completely reversed. In contrast some other pathogens tested, including Candida albicans, were relatively resistant. Thus Echinaforce) exerts a dual action against several important respiratory bacteria, a killing effect and an anti-inflammatory effect. These results support the concept of using a standardized Echinacea preparation to control symptoms associated with bacterial respiratory infections.

The requirements of protein & amino acid during acute & chronic infections.

Nutrition and infection interact with each other in a synergistic vicious cycle, leading to an adverse nutritional status and increased susceptibility to infection. Infectious episodes result in hypermetabolism and a negative nitrogen balance which is modulated by hormones, cytokines and other pro-inflammatory mediators, and is compounded by a reduced food intake. The extent of the negative nitrogen balance varies with the type of infection and its duration; however, it is reasonable to suggest that the loss of body protein could be minimized by the provision of dietary nitrogen, although anorexia will limit this. Further, distinctions need to be made about the provision of nutrients or protein during the catabolic and anabolic or recovery phase of the infection, since the capacity of the body to retain protein is enhanced in the anabolic recovery phase. Meeting the increased requirement for protein (and other nutrients) in infection does not imply a complete therapeutic strategy. Infections need to be treated appropriately, with nutrition as an adjunct to the treatment. Prior undernutrition could also impair the body's response to infection, although the weight of the evidence would suggest that this happens more particularly in oedematous undernutrition. In general, the amount of extra protein that would appear to be needed is of the order of 20-25 per cent of the recommended intake, for most infections. In acute infections, this is particularly relevant during the convalescence period. Community trials have suggested that lysine supplementation to the level required for normal daily nutriture, in predominantly wheat eating or potentially lysine deficient communities, improves immune function among other functional nutritional parameters; however, there is as yet insufficient evidence to suggest a specific requirement for amino acids in infections over and above the normal daily requirement as based on recent evidence. Some clinical studies that have showed benefits with specific amino acids through selected clinical outcomes, however, these do not provide enough evidence for a firm recommendation.

99mTc-Fanolesomab: affinity, pharmacokinetics and preliminary evaluation.

Localization of infection is critical for both diagnosis and treatment. Several radioactive compounds such as (67)Gallium citrate, (111I)ndium and (99m)Technetium-labeled leukocytes, peptides and antibodies have been used to localize sites of bacterial infection and phlegmons when anatomical imaging techniques failed. With labeled leukocytes the major concern besides the cost, was the in vitro procedure requiring more than 2 h and trained personnel to handle blood samples. Such limitations paved the way for the emergence of new agents like human immunoglobulin, interleukin-1, peptides and monoclonal antibodies. Following the intensive study of 10 monoclonal antibodies the anti SSEA-1 antibody specific for CD15 antigen was found to have a high Kd value of 1.6x10(-11) M for human neutrophils. Labeling of anti CD15 antibody (NeutroSpec) with (99m)Tc and its FDA approval was a boon to diagnostic imaging as it promised to eliminate many of the well known drawbacks of the in vitro WBC labeling. This antibody has a large number of antigenic binding sites: 5.1x10(5) per circulating human neutrophil. It has been established that very little CD15 antigen is expressed on the other blood cell lines. Upon intravenous administration to patients there was no adverse reaction except in those with underlying cardiovascular compromise or chronic pulmonary obstructive disease. Another advantage is that, this particular monoclonal antibody has not produced significant human antimouse antibody in research volunteers and patients. Twenty-four hour imaging, SPECT or planar was not required. The following pages describe the various stages of the research activity carried out towards NeutroSpec.

Imaging of infection and inflammation with 99mTc-Fanolesomab.

(99m)Tc-fanolesomab, a murine M class antigranulocyte antibody, is injected directly into patients, avoiding in vitro leukocyte labeling. Normal distribution includes reticuloendothelial system, genitourinary tract, and blood pool. Small bowel activity appears within 4 h, colonic activity by 24 h. Accumulation in infection is via two mechanisms: binding to circulating neutrophils that migrate to the infection and binding to neutrophils and neutrophil debris containing CD-15 receptors already sequestered in the infection. (99m)Tc-fanolesomab is valuable in atypical appendicitis. Its sensitivity, specificity, and accuracy, in 200 patients were 91%, 86%, and 87%, respectively. This agent is comparable to (111)In- labeled leukocytes for diagnosing osteomyelitis in the appendicular skeleton in general and in diabetic patients with pedal ulcers. Preliminary experience suggests (99m)Tc-fanolesomab might replace in vitro labeled leukocytes for other indications as well. Initial clinical investigations found the agent was safe. A transient decrease in circulating leukocytes within 20 min after injection occurred, but with no associated clinical complaints. Recovery averaged about 20 min. One study found no statistically significant HAMA titer elevation and no adverse reactions following injection. In another investigation 5 out of 30 subjects who received two separate antibody injections, exhibited HAMA induction with no serious or severe adverse events. Forty-nine adverse events, including 4 severe ones, were reported among 523 subjects in clinical trials. In 2004, (99m)Tc-falosomab was approved in the United States for use in patients with equivocal presentation of appendicitis. However, following postmarketing reports of serious adverse events, including two fatalities, the agent was withdrawn in late 2005, and its future is uncertain.

The effects of sulfur amino acid intake on immune function in humans.

No direct data exist on the influence of supranormal intakes of sulfur amino acids on immune function in humans. However 3 major products of sulfur amino acids, glutathione (GSH), homocysteine (Hcy), and taurine (Tau), influence, mainly, inflammatory aspects of the immune response in vitro and in vivo. Methionine intakes above approximately 1 g/d transiently raise plasma Tau, Hcy, and GSH. Tau and GSH ameliorate inflammation. Hcy has the opposite effect. A biphasic relation, between cellular GSH and CD4+ and CD8+ numbers occurs in healthy men. How changes in sulfur amino acid intake influence this phenomenon is unknown. In animals, high Tau intakes are antiinflammatory. How immune function in humans is affected is unknown. A positive relation between plasma neopterin (a marker of a Th-1-type immune response) and Hcy indicates that Hcy may play a part in inflammatory aspects of Parkinson's disease and aging. In vitro, Hcy, at concentrations seen following consumption of approximately 6 g L-methionine/d in adults, increases the interactions among T lymphocytes, monocytes, and endothelium. Whether a similar phenomenon occurs in vivo is unknown. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with raised plasma Hcy in young but not old subjects. The relation of this observation to immune function is unknown. The relationships among Hcy, inflammatory aspects of disease, and in vitro alterations in immune cell behavior create a cautionary note about supplementation of diets with l-methionine to raise intake above approximately 1 g/d. Studies directly linking methionine intake, genetics, plasma Hcy, Tau, and GSH and immune function are needed.

The relevance of selenium to immunity, cancer, and infectious/inflammatory diseases.

Selenium is an essential trace element involved in several key metabolic activities via selenoproteins, enzymes that are essential to protect against oxidative damage and to regulate immune function. Selenium also may have other health benefits unrelated to its enzymatic functions. It may provide important health benefits to people whose oxidative stress loads are high, such as those with inflammatory or infectious diseases like rheumatoid arthritis or human immunodeficiency virus/acquired immunodeficiency syndrome, or who are at high risk for cancers, particularly prostate cancer. Some studies have generated compelling evidence that selenium is beneficial, either alone or in conjunction with other micronutrients. Additional data from large clinical trials that provide the highest level of evidence will be key to determining the benefits accrued at various selenium intake levels. When the strength of the evidence becomes sufficient, clinical health professionals will need to use dietary and clinical assessment methods to ensure that people at increased risk for cancer or inflammatory and infectious diseases can be appropriately advised about selenium intake.

Pulmonary antioxidant concentrations and oxidative damage in ventilated premature babies.

OBJECTIVE: To determine the relation between lipid peroxidation and the antioxidants ascorbate, urate, and glutathione in epithelial lining fluid in ventilated premature babies, and to relate the biochemical findings to clinical outcome. DESIGN: A cohort study conducted between January 1999 and June 2001. SETTING: A NHS neonatal intensive care unit. PATIENTS: An opportunity sample of 43 ventilated babies of less than 32 weeks gestation. MAIN OUTCOME MEASURES: The duration of supplementary oxygen according to the definition of bronchopulmonary dysplasia (BPD; oxygen dependency at 36 weeks gestational age). METHODS: Epithelial lining fluid was sampled by bronchoalveolar lavage. Ascorbate, urate, glutathione, and malondialdehyde (a marker of lipid peroxidation) were measured. RESULTS: Babies who developed BPD had significantly lower initial glutathione concentrations (mean (SEM) 1.89 (0.62) v 10.76 (2.79) microM; p = 0.043) and higher malondialdehyde concentrations (mean (SEM) 1.3 (0.31) v 0.345 (0.09) microM; p < 0.05) in the epithelial lining fluid than those who were not oxygen dependent. These variables were poor predictors of the development of BPD. Gestational age, endotracheal infection, and septicaemia had good predictive power. The level of oxidative damage was associated with the presence of endotracheal infection/septicaemia rather than inspired oxygen concentration. CONCLUSIONS: Endotracheal infection, septicaemia, and gestational age, rather than antioxidant concentrations, are the most powerful predictors of the development of BPD.

Nitric oxide, human diseases and the herbal products that affect the nitric oxide signalling pathway.

1. Nitric oxide (NO) is formed enzymatically from l-arginine in the presence of nitric oxide synthase (NOS). Nitric oxide is generated constitutively in endothelial cells via sheer stress and blood-borne substances. Nitric oxide is also generated constitutively in neuronal cells and serves as a neurotransmitter and neuromodulator in non-adrenergic, non-cholinergic nerve endings. Furthermore, NO can also be formed via enzyme induction in many tissues in the presence of cytokines. 2. The ubiquitous presence of NO in the living body suggests that NO plays an important role in the maintenance of health. Being a free radical with vasodilatory properties, NO exerts dual effects on tissues and cells in various biological systems. At low concentrations, NO can dilate the blood vessels and improve the circulation, but at high concentrations it can cause circulatory shock and induce cell death. Thus, diseases can arise in the presence of the extreme ends of the physiological concentrations of NO. 3. The NO signalling pathway has, in recent years, become a target for new drug development. The high level of flavonoids, catechins, tannins and other polyphenolic compounds present in vegetables, fruits, soy, tea and even red wine (from grapes) is believed to contribute to their beneficial health effects. Some of these compounds induce NO formation from the endothelial cells to improve circulation and some suppress the induction of inducible NOS in inflammation and infection. 4. Many botanical medicinal herbs and drugs derived from these herbs have been shown to have effects on the NO signalling pathway. For example, the saponins from ginseng, ginsenosides, have been shown to relax blood vessels (probably contributing to the antifatigue and blood pressure-lowering effects of ginseng) and corpus cavernosum (thus, for the treatment of men suffering from erectile dysfunction; however, the legendary aphrodisiac effect of ginseng may be an overstatement). Many plant extracts or purified drugs derived from Chinese medicinal herbs with proposed actions on NO pathways are also reviewed.