Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease

Human respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract disease (LRTD) in young children worldwide. Extensive neutrophil accumulation in the lungs and occlusion of small airways by DNA‐rich mucus plugs are characteristic features of severe RSV–LRTD. Activated neutrophils can release neutrophil extracellular traps (NETs), extracellular networks of DNA covered with antimicrobial proteins, as part of the first‐line defence against pathogens. NETs can trap and eliminate microbes; however, abundant NET formation may also contribute to airway occlusion. In this study, we investigated whether NETs are induced by RSV and explored their potential anti‐viral effect in vitro. Second, we studied NET formation in vivo during severe RSV–LRTD in infants and bovine RSV–LRTD in calves, by examining bronchoalveolar lavage fluid and lung tissue sections, respectively. NETs were visualized in lung cytology and tissue samples by DNA and immunostaining, using antibodies against citrullinated histone H3, elastase and myeloperoxidase. RSV was able to induce NET formation by human neutrophils in vitro. Furthermore, NETs were able to capture RSV, thereby precluding binding of viral particles to target cells and preventing infection. Evidence for the formation of NETs in the airways and lungs was confirmed in children with severe RSV–LRTD. Detailed histopathological examination of calves with RSV–LRTD showed extensive NET formation in dense plugs occluding the airways, either with or without captured viral antigen. Together, these results suggest that, although NETs trap viral particles, their exaggerated formation during severe RSV–LRTD contributes to airway obstruction. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Long-term follow-up of depression among patients in the community and in family practice settings. A systematic review

BACKGROUND: Current knowledge about the long-term outcome of depression is largely based on the results of studies performed with the small selection of patients who are referred to psychiatric professionals. However, because of the high prevalence of depression in the community and in primary care, information about the longterm outcome in these populations is indispensable if physicians are to offer the best possible care in these settings. METHODS: We performed a literature search to identify relevant papers published between 1970 and 1999 on original long-term follow-up studies of depression in community and primary care populations. The included studies were of adult populations with depression based on diagnostic criteria and a follow-up of at least 5 years. Data about recurrences, relapses, psychopathology, disability, or quality of life at follow-up were examined. RESULTS: We found 8 studies that fulfilled our criteria. The reported rates of recurrence or depression at follow-up were between 30% and 40%. Higher rates were found in the younger and older age groups. Data about other predictors of outcome, health status, and the relation between treatment and outcome did not justify any hard conclusions. CONCLUSIONS: The long-term outcome of depression in the community and in primary care is rarely studied. The results of available studies are difficult to compare because of the large differences in populations and methods. Nevertheless, these studies suggest that the longterm prognosis of depression in the community and in primary care is not as poor as in psychiatry.     

HIV infection in haemophilia--a European cohort

Ten haemophilia centres in northern Europe have pooled data on 202 haemophilic children who were infected with HIV between 1979 and 1986. All cases were under 16 years of age on 1 July 1985. The age at infection ranged from 1-15 years. Thirty seven cases (18%) had progressed to AIDS by 1 July 1991 and 15 of these have died. Persistent generalised lymphadenopathy has been noted in 102 patients of whom 18 (17%) have developed AIDS. Twenty three of the remaining patients (23%) have not. CD4+ T cell counts have fallen steadily. Of 36 patients who have had shingles since seroconversion, 19 (53%) had counts below 0.2 x 10(9)/l. Thirty five out of 145 patients without shingles (24%) had similar values. The mean IgA concentration in patients with CD4+ T cell counts above 0.5 x 10(9)/l was 2.38 g/l, between 0.2 and 0.5 was 3.07 g/l, and in those with CD4+ T cell counts below 0.2 x 10(9)/l the mean IgA concentration was 4.58 g/l. Treatment patterns have altered between 1989 and 1991, with increased use of zidovudine in patients without AIDS and a marked increase in primary prophylaxis against pneumocystis pneumonia. This has been associated with a decline in the incidence of pneumocystis as an indicator disease in new AIDS cases from 56% in 1989 to 20% in 1991. These observations indicate that persistent generalised lymphadenopathy does not worsen the outlook, but shingles does. Rising IgA concentrations are markers for disease progression. Modern prophylactic regimens are delaying the onset of indicator disease, but CD4 values continue to fall steadily.     

Ageing in adults with Down's syndrome in institutionally based and community-based residences

Seventy-one subjects with Down's syndrome (DS), between the ages of 29 and 68 years, and 46 matched controls (without DS) were examined for intelligence, memory (short- and long-term memory, and spatial and temporal orientation), communication (receptive, expressive and written language) and daily living skills (personal, domestic and community daily living skills). All subjects were screened on hearing and visual functions, thyroid functions; depression and dementia. DS-subjects and controls were matched on chronological age, mental age, living conditions and male/female ratio. Comparisons were made between five subgroups (I) non-demented institutionalized subjects with DS (DSI-group; n=35); (2) non-demented institutionalized controls without DS (Ci-group; n=22); (3) demented institutionalized subjects with DS (n= 10); (4) non-demented subjects with DS living in group homes (DSg; n=26); and (5) non-demented controls without DS living in group homes (Cg; n=24). Institutionalized and non-institutionalized subjects, as well as demented and non-demented subjects differed significantly on all functions measured. Multiple regression analysis was performed to examine the influence of age and sensory deficits on adaptive and cognitive functioning. In DSg subjects, significant associations were found between age and mental age, and between age and performances on written language. In (non-demented) DSi subjects, significant relations were found between age and memory functions observed in daily circumstances. Moreover, in the (non-demented) DSi elderly, visual impairment was significantly related to depressed performance on daily living skills. No age effects were seen in control subjects. Infirmities of old age like dementia and sensory deficits were far more common in people with DS than in controls. Psychiatric and diagnostic aspects of clinical depression and dementia were emphasized in particular.     

Cellular PSA in benign and malignant prostate

To determine the relationship of carcinoma of the prostate and cellular production of prostate-specific antigen, cytosol levels of PSA were measured in benign and malignant fresh prostate tissue harvested from radical prostatectomy specimens. Wedge biopsies were taken from benign (N = 21) and malignant (N = 74) prostate tissue and were immediately fixed in liquid nitrogen, and then homogenized and differentially centrifuged, and the cytosol fractions extracted. The remaining specimen was sent for routine pathologic assessment. The Hybritech methodology was used to measure the cytosol PSA and standard protein analysis was used for cytosol protein (CP) measurement. There was a significantly greater concentration of PSA in malignant tissue (P = 0.046). Also, when benign and malignant tissue were available from a single prostate (N = 17), these differences in cytosol PSA were even greater (P = 0.002). In addition, there was no significant difference when serum PSAs from the malignant tissue were ranked according to Gleason score and placed into three different histologic grades (i.e., Gleason scores 2–4, 5–6, and 7–10).     

Determination of the benzodiazepine plasma concentrations in suicidal patients using a radioreceptor assay

Impairments in memory and psychomotor function appear to be induced by benzodiazepines not only after long-term use, but also after administration of a single dose. Because it is known on which neurotransmitter system the benzodiazepines exert their action, the use of a quantitative radioreceptor assay (RRA) can be a useful tool in studying the interrelationship between the neurochemical and memory processes. The RRA measures the sum of the main compound(s) and all active metabolites present, where it relates the biological activity to the pharmacodynamic effect instead of relating it to the plasma levels of the individual compounds. To correlate the loss of memory with the benzodiazepine concentration, plasma concentrations were determined in suicidal patients. From suicidal patients (n = 84), the benzodiazepines in plasma were measured with a direct radioreceptor assay using tritiated flunitrazepam as the labelled ligand. The receptor material was a lyophilized preparation from calf cortex. Furthermore, the samples were subjected to high-performance liquid chromatographic (HPLC) analysis, and the HPLC data were converted to diazepam equivalents using cross-reactivities of the individual compounds. Patients who had ethanol residues in their plasma were excluded from this correlation experiment. The data (n = 40) obtained with the two analytical techniques were compared and correlated to assess the validity of the radioreceptor assay in establishing the relationship between the loss of memory and the total amount of benzodiazepines present. The cumulative amount of diazepam determined with the RRA and the sum of compounds determined with the HPLC method, after correction using the cross-reactivities, were plotted and correlated using regression analysis. Regression analysis showed an x variable of 0.75 and a correlation coefficient of 0.67. The intercept was not significantly different from zero (P = 0.49, t-test), whereas the slope was significantly different from zero (P < 0.01). Benzodiazepines can be directly determined in plasma using this radioreceptor assay. The data obtained from HPLC analysis were easily converted to diazepam equivalents using the cross-reactivities. A discrepancy between the data obtained from the two analytical techniques, however, indicates that certain metabolites are present, which were not quantitated in the HPLC analysis, but were measured in the radioreceptor assay. Therefore, the radioreceptor assay proved to be a valuable tool for the assessment of clinical effects, such as the demonstration of the loss of memory in suicidal patients after a benzodiazepine overdose.     

Psychomotor, neuroendocrine and behavioural effects after oral administration of levodopa in normal volunteers

The oral administration of a single dose of levodopa (L-dopa) in 10 healthy human male subjects induced cognitive, not motor, changes during figure-copying tasks that were unrelated to the neuroendocrine and behavioural effects of levodopa. Results point to a decrease in alertness induced by levodopa.     

Treatment methods for discontinuation of long-term benzodiazepine use

Treatment strategies for discontinuing long-term benzodiazepine usage can be divided into minimal interventions and gradual discontinuation programs. Minimal interventions invite patients to quit their long-term benzodiazepine usage on their own by making them aware of the adverse effects. This type of intervention is successful in about one fifth of patients. Gradual discontinuation programs are more extensive interventions in order to help those patients who are unable to discontinue benzodiazepine use on their own. These programs are successful in two-thirds of the patients and can be combined with additional pharmacological or psychological treatment. Once the withdrawal symptoms have diminished, most patients have an improved psychological functioning compared to when they were using benzodiazepines. Furthermore, no increase in medical consumption has been found.