Longitudinal profiling of plasma cytokines in melioidosis and their association with mortality: a prospective cohort study.

OBJECTIVES: To characterize plasma cytokine responses in melioidosis and analyse their association with mortality. METHODS: A prospective longitudinal study was conducted in two hospitals in Northeast Thailand to enrol 161 individuals with melioidosis, plus 13 uninfected healthy individuals and 11 uninfected individuals with diabetes to act as controls. Blood was obtained from all individuals at enrolment (day 0), and at days 5, 12 and 28 from surviving melioidosis patients. Interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-23, and tumour necrosis factor-α (TNF-α) were assayed in plasma. The association of each cytokine and its dynamics with 28-day mortality was determined. RESULTS: Of the individuals with melioidosis, 131/161 (81%) were bacteraemic, and 68/161 (42%) died. On enrolment, median levels of IFN-γ, IL-6, IL-8, IL-10, IL-23 and TNF-α were higher in individuals with melioidosis compared with uninfected healthy individuals and all but IFN-γ were positively associated with 28-day mortality. Interleukin-8 provided the best discrimination of mortality (area under the receiver operating characteristic curve 0.78, 95% CI 0.71-0.85). Over time, non-survivors had increasing IL-6, IL-8 and IL-17A levels, in contrast to survivors. In joint modelling, temporal trajectories of IFN-γ, IL-6, IL-8, IL-10 and TNF-α predicted survival. CONCLUSIONS: In a severely ill cohort of individuals with melioidosis, specific pro- and anti-inflammatory and T helper type 17 cytokines were associated with survival from melioidosis, at enrolment and over time. Persistent inflammation preceded death. These findings support further evaluation of these mediators as prognostic biomarkers and to guide targeted immunotherapeutic development for severe melioidosis.

Melioidosis in patients with suspected tuberculosis in Cambodia: a single-center cross-sectional study.

SETTING: Melioidosis-Burkholderia pseudomallei infection-is increasingly recognized in Cambodia, a country with a high incidence of tuberculosis (TB). Melioidosis and TB can be clinically indistinguishable. OBJECTIVE: To quantify the proportion of patients with clinically suspected TB who had melioidosis by testing sputum for B. pseudomallei. DESIGN: This was a prospective, 6-month cross-sectional single-center study at a Cambodian provincial referral hospital among patients with suspicion of TB who provided sputum specimens for testing. TB was diagnosed using sputum Xpert® MTB/RIF molecular assay or culture; melioidosis was diagnosed using sputum culture for B. pseudomallei. RESULTS: Of 404 patients evaluated for possible TB, 52 (12.9%, 95%CI 9.8-16.5) had TB. Four patients (1.0%, 95%CI 0.3-2.5) had melioidosis; none had concurrent TB or an existing medical risk factor for melioidosis, although two were farmers, an occupational risk factor. CONCLUSION: One per cent of patients being evaluated for TB at a Cambodian provincial referral hospital had culture-proven respiratory melioidosis, a highly lethal infection. None had previously recognized medical conditions that would increase their risk of melioidosis. Testing for melioidosis should be considered in patients presenting with suspected TB in Cambodia.

TLR4 genetic variation is associated with inflammatory responses in Gram-positive sepsis.

OBJECTIVES: To identify important pathogen recognition receptor (PRR) pathways regulating innate immune responses and outcome in Staphylococcus aureus sepsis. METHODS: We analysed whether candidate PRR pathway genetic variants were associated with killed S. aureus-induced cytokine responses ex vivo and performed follow-up in vitro studies. We tested the association of our top-ranked variant with cytokine responses and clinical outcomes in a prospective multicentre cohort of patients with staphylococcal sepsis. RESULTS: An intronic TLR4 polymorphism and expression quantitative trait locus, rs1927907, was highly associated with cytokine release induced by stimulation of blood from healthy Thai subjects with S. aureus ex vivo. S. aureus did not induce TLR4-dependent NF-κB activation in transfected HEK293 cells. In monocytes, tumor necrosis factor (TNF)-α release induced by S. aureus was not blunted by a TLR4/MD-2 neutralizing antibody, but in a monocyte cell line, TNF-α was reduced by knockdown of TLR4. In Thai patients with staphylococcal sepsis, rs1927907 was associated with higher interleukin (IL)-6 and IL-8 levels as well as with respiratory failure. S. aureus-induced responses in blood were most highly correlated with responses to Gram-negative stimulants whole blood. CONCLUSIONS: A genetic variant in TLR4 is associated with cytokine responses to S. aureus ex vivo and plasma cytokine levels and respiratory failure in staphylococcal sepsis. While S. aureus does not express lipopolysaccharide or activate TLR4 directly, the innate immune response to S. aureus does appear to be modulated by TLR4 and shares significant commonality with that induced by Gram-negative pathogens and lipopolysaccharide.

Comparison of community-onset Staphylococcus argenteus and Staphylococcus aureus sepsis in Thailand: a prospective multicentre observational study.

Staphylococcus argenteus is a globally distributed cause of human infection, but diagnostic laboratories misidentify this as Staphylococcus aureus. We determined whether there is clinical utility in distinguishing between the two. A prospective cohort study of community-onset invasive staphylococcal sepsis was conducted in adults at four hospitals in northeast Thailand between 2010 and 2013. Of 311 patients analysed, 58 (19%) were infected with S. argenteus and 253 (81%) with S. aureus. Most S. argenteus (54/58) were multilocus sequence type 2250. Infection with S. argenteus was more common in males, but rates of bacteraemia and drainage procedures were similar in the two groups. S. argenteus precipitated significantly less respiratory failure than S. aureus (5.2% versus 20.2%, adjusted OR 0.21, 95% CI 0.06-0.74, p 0.015), with a similar but non-significant trend for shock (6.9% versus 12.3%, adjusted OR 0.46, 95% CI 0.15-1.44, p 0.18). This did not translate into a difference in death at 28 days (6.9% versus 8.7%, adjusted OR 0.80, 95% CI 0.24-2.65, p 0.72). S. argenteus was more susceptible to antimicrobial drugs compared with S. aureus, and contained fewer toxin genes although pvl was detected in 16% (9/58). We conclude that clinical differences exist in association with sepsis due to S. argenteus versus S. aureus.

Screen of whole blood responses to flagellin identifies TLR5 variation associated with outcome in melioidosis.

Melioidosis is a severe infection caused by the flagellated bacterium Burkholderia pseudomallei. The nonsense polymorphism TLR51174C>T is associated with improved outcome in Thais with melioidosis. We hypothesized that other TLR5 variants may modulate the host response and determine outcome in melioidosis. We genotyped 12 TLR5 variants selected de novo from the HapMap database and examined the association of each with cytokines induced by flagellin stimulation of whole blood from healthy Thai subjects. We found a blunted cytokine response for three related markers that were in linkage disequilibrium (LD) with a non-synonymous variant, TLR51846T>C. Carriers of TLR51846T>C had broadly impaired cytokine responses induced by flagellin. TLR51846T>C was associated with protection against death in melioidosis patients (odds ratio: 0.62, 95% confidence interval: 0.42-0.93, P=0.021). We observed no impairment in TLR51846C-dependent nuclear factor κB activation, however, suggesting an alternative mechanism for the effect. We found that TLR51846T>C was in strong LD with TLR51174C>T. Many of the blunted cytokine responses observed and the association of TLR51846T>C with survival in melioidosis patients may be attributable to TLR51174C>T, but we could not exclude an independent effect of TLR51846T>C. These data identify novel associations for TLR51846T>C, enhance our understanding of TLR5 genetic architecture in Thais and highlight the role of TLR5 in melioidosis.

Toll-like receptor 4 region genetic variants are associated with susceptibility to melioidosis.

Melioidosis is a tropical infection caused by the Gram-negative soil saprophyte Burkholderia pseudomallei. Despite broad exposure of northeastern Thais, disease develops in only a small proportion of individuals. Although diabetes is a risk factor, the mechanisms of host susceptibility to melioidosis are still poorly understood. We postulated that Toll-like receptors (TLRs) regulate host susceptibility to disease, and that genetic variation in TLRs is associated with melioidosis. We analyzed the frequency of eight previously described TLR pathway polymorphisms in 490 cases compared with 950 non-hospitalized controls or 458 hospitalized controls. Based on these results, we then analyzed the frequency of additional TLR4 or TLR6-1-10 region polymorphisms in cases and controls. We found that the TLR4(1196C>T) variant was associated with protection from melioidosis when compared with non-hospitalized controls. The TLR1(742A>G) and TLR1(-7202A>G) variants were associated with melioidosis when compared with hospitalized controls. In further analyses, we found that two additional TLR4 region polymorphisms were associated with disease. In diabetics, three other TLR6-1-10 region polymorphisms were associated with disease when compared with hospitalized controls. We conclude that TLR genetic variants may modulate host susceptibility to melioidosis. Confirmation of these findings and further investigation of the mechanisms are required.

Challenges and solutions of remote sensing at offshore wind energy developments.

Radar is becoming an important tool used to gather data on bird and bat activity at proposed and existing land-based wind energy sites. Radar will likely play an even more important role at the increasing development of wind energy offshore, given both the lack of knowledge about bird and bat activity offshore and the increased difficulty in obtaining offshore information. Most radar studies to date have used off-the-shelf or modified marine radars. However, there are several issues that continue to hinder the potential usefulness of radar at wind energy sites, with offshore sites providing a particular suite of challenges. We identify these challenges along with current or developing solutions.

An unusual cause of severe hypoglycaemia in type 1 diabetes mellitus. Antepartum pituitary failure: a case report and literature review.

We describe an unusual cause of severe hypoglycaemia, secondary to hypopituitarism as a result of antepartum pituitary failure, in a pregnant patient with type 1 diabetes mellitus (T1DM). Antepartum pituitary failure is a very rare condition, which has been reported only in a very small number of pregnant patients with diabetes and presents with an acute onset headache and a sub-arachnoid haemorrhage-like picture. It is a potentially fatal condition to the mother and the child if not recognised and treated. Our case report highlights the importance of thinking about hypopituitarism, as a cause of recurrent hypoglycaemia in pregnant patients with T1DM as missing the diagnosis could be fatal to the mother and child.

[Frequency of occurrence of Hepatitis C virus markers and risk factors among hospital personnel in the Novosibirsk region]. / Chastota vstrechaemosti markerov gepatita C i faktory riska u personala bol'nits Novosibirskoi oblasti.

The occurrence of markers, the genotypic variety of isolates and the profile of risk factors with respect to viral hepatitis C among 629 employees of the Regional Clinical Hospital (RCH) in Novosibirsk and 1,020 employees of the Central District Hospital (CDH) in Iskitim were studied in a cross-sectional investigation. The occurrence of hepatitis C virus (HCV) markers was 5.1% in RCH and 2.2% in CDH. Among the risk factors in the population under study were: the medical history of blood transfusions (TF) with 0 TF, anti-HCV = 2.3%; 1 TF, = 5.7% > 1 TF, = 13.5% (p < 0.001); general anesthesia (GA) with < or = 2 GA, anti-HCV = 2.8%; > 2 GA, = 7.8% (p = 0.002); surgical interventions (SU) with 0 SU, = 1.9%; > 0 SU, = 4.3% (p = 0.012); the intravenous use of drugs (OR = 31.8); age (< or = 25 years, anti-HCV IgG = 8.6% > 25 years, = 4.5%); the number of partners of the opposite sex < or = 4 partners, = 2.4%; > 4 partners, = 6.9%; p < 0.001). The probable risk factors at a working place (pricks and cuts, contamination of mucous membranes with blood and other biological fluids, etc.) proved to be faintly related with the status of HBV infection. HBV isolates detected in the examined persons (35 examinees) were distributed by genotypes as follows: 60% of subtype 1b, 28.6% of subtype 2a/2c, 11.4% of subtype 3a. HBV of genotype 1a was not detected in the examined specimens, while the detection rate of genotype 2a/2c was considerably greater than in specimens obtained in the European and Asian parts of Russia (according to the data reported earlier).

Outcome of meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae type b in children in The Gambia.

In developing countries, endemic childhood meningitis is a severe disease caused most commonly by Streptococcus pneumoniae or Haemophilus influenzae type b (Hib). Although many studies have shown that fatality rates associated with meningitis caused by these organisms are high in developing countries, little is known about the long-term outcome of survivors. The purpose of this study was to assess the importance of disabilities following pneumococcal and Hib meningitis in The Gambia. 257 children aged 0-12 years hospitalized between 1990 and 1995 with culture-proven S. pneumoniae (n = 134) or Hib (n = 123) meningitis were included retrospectively in the study. 48% of children with pneumococcal meningitis and 27% of children with Hib meningitis died whilst in hospital. Of the 160 survivors, 89 (55%) were followed up between September 1996 and October 1997. Of the children with pneumococcal meningitis that were traced, 58% had clinical sequelae; half of them had major disabilities preventing normal adaptation to social life. 38% of survivors of Hib meningitis had clinical sequelae, a quarter of whom had major disabilities. Major handicaps found were hearing loss, mental retardation, motor abnormalities and seizures. These data show that despite treatment with effective antibiotics, pneumococcal and Hib meningitis kill many Gambian children and leave many survivors with severe sequelae. Hib vaccination is now given routinely in The Gambia; an effective pneumococcal vaccine is needed.

Long-term morbidity and mortality following hypoxaemic lower respiratory tract infection in Gambian children.

Acute lower respiratory infections (ALRI) are the main cause of death in young children worldwide. We report here the results of a study to determine the long-term survival of children admitted to hospital with severe pneumonia. The study was conducted on 190 Gambian children admitted to hospital in 1992-94 for ALRI who survived to discharge. Of these, 83 children were hypoxaemic and were treated with oxygen, and 107 were not. On follow-up in 1996-97, 62% were traced. Of the children with hypoxaemia, 8 had died, compared with 4 of those without. The mortality rates were 4.8 and, 2.2 deaths per 100 child-years of follow-up for hypoxaemic and non-hypoxaemic children, respectively (P = 0.2). Mortality was higher for children who had been malnourished (Z-score < -2) when seen in hospital (rate ratio = 3.2; 95% confidence interval (CI) = 1.03-10.29; P = 0.045). Children with younger siblings experienced less frequent subsequent respiratory infections (rate ratio for further hospitalization with respiratory illness = 0.15; 95% CI = 0.04-0.50; P = 0.002). Children in Gambia who survive hospital admission with hypoxaemic pneumonia have a good prognosis. Survival depends more on nutritional status than on having been hypoxaemic. Investment in oxygen therapy appears justified, and efforts should be made to improve nutrition in malnourished children with pneumonia.

PIP: Acute lower respiratory infections (ALRI) are the main cause of death among children under 5 years old worldwide. Findings are reported from a study conducted to assess the long-term survival of 190 Gambian children under age 5 years admitted to the Royal Victoria Hospital, Banjul, in 1992-94, with severe pneumonia who survived to discharge. 83 of the children were hypoxemic and treated with oxygen. 118 (62%) subjects were traced on follow-up in 1996-97. Of the children with hypoxemia, 8 died, compared to 4 who did not have the condition. Mortality rates were 4.8 and 2.2 deaths per 100 child-years of follow-up for hypoxemic and nonhypoxemic children, respectively. The level of mortality was higher among children who had been malnourished when seen in hospital, while children with younger siblings experienced less frequent subsequent respiratory infections. These findings suggest that children in Gambia who survive hospital admission with hypoxemic pneumonia have a good prognosis. Survival depends more upon nutritional status than upon having been hypoxemic. Investment in oxygen therapy seems justified, and efforts should be made to improve nutrition in malnourished children with pneumonia.

The dexamethasone suppression test and treatment outcome in elderly depressed patients participating in a placebo-controlled multicenter trial involving moclobemide and nortriptyline.

The dexamethasone suppression test (DST) was conducted in 95 elderly DSM-III-R depressed patients randomized for treatment with moclobemide (MOC; 400 mg daily), nortriptyline (NT; 75 mg daily), or placebo (PBO) in a 7-week double-blind multicenter study. Patients were assessed weekly using various clinical scales, including the 17-item Hamilton Depression Rating Scale. The DST was administered at baseline and at the end of treatment. At baseline, no relationship was found between DST status and the various clinical scales used. At the end of treatment, suppressors (DST-) had significantly improved clinical ratings compared to nonsuppressors (DST+), and were mostly found among those treated with NT (71%) as compared to MOC (41%) or PBO (33%) (p < .03). On the other hand, baseline DST measures influenced treatment outcome; DST+ patients had a greater number of treatment responders to NT (48%) than MOC (19%) or PBO (20%) (p < .07). For DST- patients, the situation was reversed: NT, 7%; MOC, 31%. Postdexamethasone cortisol levels were lower in MOC responders (p < .07). An interaction was found between DST and drug-specific response. The DST may be a useful adjunct for predicting and evaluating the outcome of antidepressant therapy.

Comparison of fluvoxamine, imipramine, and placebo in the treatment of outpatients with panic disorder.

Fluvoxamine and imipramine were compared to placebo in an 8-week doubleblind randomized multicentre trial comprising of 148 outpatients between 19 and 57 years of age (mean: 35) with a DSM-III-R diagnosis of Panic Disorder. mean daily dose at endpoint was: fluvoxamine, 171.4 mg; imipramine 164.7 mg. The mean number of panic attacks per week at baseline were 10.9, 14.4 and 6.5 for fluvoxamine, imipramine and placebo, respectively. The intent-to-treat analysis of the change from baseline (difference score) of the number of panic attacks at endpoint revealed: a difference of 3.3 attacks (95% CI: -0.3, 6.8) between fluvoxamine and placebo and a difference of 6.0 attacks (95% CI: 1.5, 10.5) between imipramine and placebo. Treatment was stopped prematurely in 31 (62%) on fluvoxamine, 16 (33%) on imipramine and 29 (58%) on placebo. The number of patients withdrawing due to intolerance was 13 (26%) for fluvoxamine, 10 (21%) for imipramine and 4 (8%) for placebo. The number of patients withdrawing due to lack of efficacy was 10 (20%) for fluvoxamine, 4 (8%) for imipramine and 12 (24%) for placebo. Overall, this study demonstrated that fluvoxamine was not effective in the treatment of panic disorder but did show a strong effect for imipramine. A chance occurrence of significantly fewer number of panic attacks in the placebo group at baseline may limit the conclusions of this study.

Peripartum hypopituitarism and lymphocytic hypophysitis.

The classical cause of postpartum hypopituitarism is Sheehan's syndrome, in which an obstetric catastrophe is associated with hypotension. However, with improvements in obstetric care, the most common cause now may be lymphocytic hypophysitis. Five women with postpartum hypopituitarism, whose symptoms occurred during or immediately after pregnancy, had detailed endocrine and pituitary imaging for the duration of follow-up. Two presented with visual symptoms, and three with non-specific illnesses related to varying deficiencies of anterior pituitary hormones. Four were unable to lactate, and four were initially amenorrhoeic. Initially, four of the five women had enlarged pituitary glands on magnetic resonance imaging. Four have to some extent recovered pituitary function. One patient had associated thyroiditis: in two cases antinuclear antibodies became positive during follow-up, and in one of these dsDNA antibody was also detected. In no case were pituitary antibodies detected. None had complicated pregnancies or deliveries, and the two who had caesarean sections had no episodes of hypotension. The presentation of secondary hypothyroidism combined with ACTH deficiency in four of the five women strongly suggests lymphocytic hypophysitis. This diagnosis should be considered in postpartum women with general malaise and persistent amenorrhoea, as well as in women who develop visual impairment in the last trimester of pregnancy without antecedent pituitary disease. A conservative policy of management of the pituitary enlargement should be pursued as this resolves.

Reversible and selective inhibitors of monoamine oxidase A in the treatment of depressed elderly patients.

The treatment of depression in the elderly population needs a thorough and careful work-up and an aggressive therapeutic approach. Any treatment initiative in this population often becomes difficult because of accompanying physical illness, concomitant medication, possible degenerative changes in central nervous system and age-related altered metabolic status. Despite unevenness in research findings, pharmacological treatment remains the mainstay of management of depression among elderly people. Currently available antidepressants, although effective, are problematic because of the increased vulnerability of the elderly to side effects. Recent research efforts to improve the efficacy and safety of drug treatment of depression resulted in development of reversible and selective monoamine oxidase inhibitors of the isoenzyme A (RIMA), with antidepressant efficacy comparable to tricyclic antidepressants and newer generation antidepressants. RIMAs include moclobemide, brofaromine, toloxatone and cimoxatone. Moclobemide is the most investigated available RIMA for therapeutic use at present. Its absorption and disposition in elderly individuals do not differ significantly from those in young healthy volunteers and depressed patients. The results of present clinical studies show that, in elderly depressed patients, moclobemide is at least as effective as other antidepressants. Its particular advantage is, however, that it is as well tolerated in elderly people as in younger people. There are only few significant adverse events, and they are generally less frequent and less severe than those with TCAs. An additional attribute of moclobemide seems also to be its beneficial effect on cognitive functions.

Multidimensional work sampling to study the activities of decentralized clinical pharmacists.

Self-reported multidimensional work sampling (MDWS) was used to study the activities of decentralized clinical pharmacists at six hospitals in Portland, Oregon, and Seattle-Tacoma, Washington, in March through June 1989. A community hospital, a university hospital, and a hospital associated with a health maintenance association were selected in each city, and pharmacists at each site who provided clinical services were recruited. Each pharmacist wore a random reminder device and recorded the activity during which the device sounded by writing on a card numbers assigned to describe work activity, contact, location, and function. Of 6609 classifiable observations, 34.5% (2280) were of clinical activities and 35.8% distributive activities. Pharmacists spent 28.6% of their clinical time reviewing and assessing patients' charts, 17.1% on clinical rounds, 15.9% on activities related to therapeutic drug monitoring, 10.2% providing drug information, 11.6% attending or giving formal education, 6.1% doing research, and 2.6% attending meetings. The average pharmacist spent less than 10 minutes each day with patients but spent a substantial portion of time providing clinical services to other health professionals. Self-reported, multidimensional work sampling appears to be a valuable method for describing and monitoring decentralized pharmacists' work activities at multiple sites and work settings.

Ventral pallidal microinjections of receptor-selective opioid agonists produce differential effects on circling and locomotor activity in rats.

Locomotor activity was investigated following microinjections of receptor-selective opioid agonists into the ventral pallidum (VP) of rats. In Expt. 1, male Long-Evans rats were treated with unilateral microinjections of the mu agonist [D-Ala2-MePhe4, Gly-ol5]-enkephalin (DAGO), the delta agonist [D-Pen2, D-Pen5]-enkephalin (DPDPE) or the kappa agonist U50,488H, and the rate and duration of circling behaviour were measured. DAGO (0.01, 0.1, 1.0 nmol) produced a dose-dependent increase in contralateral circling; pretreatment with 1.0 mg/kg naltrexone blocked the circling induced by the highest dose. The behavioral effect was largest when injections were targeted at the VP rather than structures dorsal to the VP. In contast to DAGO, intrapallidal DPDPE (0.01, 0.1, 1.0, 10.0 nmol) produced a slight increase in contralateral circling only at the highest dose and U50, 488H (0.01, 0.1, 1.0, 10.0 nmol) produced no effect. In Expt. 2, the effects of bilateral injections of DAGO, DPDPE and U50,488H were tested in photocell activity boxes. DAGO produced a dose-dependent increase in locomotor activity and this increase was decreased by 1.0 mg/kg naltrexone. A slight increase in activity was observed with the highest dose of DPDPE, and a slight decrease was observed with the highest dose of U50,488H. These findings confirm that opiate actions in the VP contribute to opiate-induced locomotion and suggest that mu and to some extent delta receptors are involved in this behavior.