Multifocal haemorrhagic brain damage following hypoxia and blood pressure lability: case report and rat model

P. S. Pahlavan, W. Sutton, R. J. Buist and M. R. Del Bigio (2012) Neuropathology and Applied Neurobiology 38 , 723–733 Multifocal haemorrhagic brain damage following hypoxia and blood pressure lability: case report and rat model Aims: Haemorrhagic brain damage is frequently encountered as a complication of premature birth. Much less frequently, multifocal petechial haemorrhage is identified in asphyxiated term newborns. Our goal was to develop an experimental rat model to reproduce this pattern of brain damage. Methods: Neonatal rat pups were exposed to a 24‐h period of 10% or 8% hypoxia followed by a single dose of phenylephrine. Acute and subacute changes, as well as long‐term outcomes, were investigated by histology, brain magnetic resonance imaging and behavioural assessment. Immunostaining for vascular endothelial growth factor and caveolin‐1 was performed in the rat brains as well as in a 17‐day human case. Results: Small foci of haemorrhage were identified in almost all regions of the rat brain subjected to hypoxia plus phenylephrine, but not hypoxia alone. Exposure to 8% hypoxia was associated with more haemorrhagic foci than 10% hypoxia. With rare exceptions, the blood deposits were too small to be detected by magnetic resonance imaging. Altered immunohistochemical detection of vascular endothelial growth factor and caveolin‐1 in the child and the rat model suggests a role for blood–brain barrier compromise. There were no clear behavioural changes and no residual morphological abnormalities in the 78‐day follow‐up of the rats. Conclusions: We conclude that transient hypoxia, in a dose‐dependent manner, can weaken the vasculature and predispose to brain haemorrhage in the situation of labile blood pressure. Persistent hypoxia is likely to be important in the genesis of permanent severe brain damage.     

Impact of hormone therapy on false-positive recall and costs among women undergoing screening mammography

OBJECTIVE: We sought to evaluate the effects of hormone therapy (HT) on false-positive (FP) recall for additional breast evaluation and costs. DESIGN: We undertook an observational cohort study of women ages 40-80 years with 2 mammography screenings in an integrated delivery system. MEASURES: FP recall, defined as mammograms resulting in a radiologist's recommendation for additional imaging, ultrasound, or invasive procedures among disease-free women, was compared for nonusers, initiators, discontinuers, and continuers of HT. Differences in health care costs by HT were assessed for total, primary care, specialty, laboratory, radiology, inpatient, mental health, and pharmacy. RESULTS: There was no association between HT and FP recall among women ages 40-49 years. Among women 50 years or older, current HT users, ie, initiators and continuers, had increased odds of FP recall (odds ratio; 95% confidence interval) compared with nonusers (1.2; 1.0-1.4 for women 50-59 years; 1.8; 1.5-2.2 for women 60-69; and 1.7; 1.4-2.0 for women 70-80 years). Among women 50-59 years, the odds of FP recall were attributed to opposed HT (ie, estrogen+progestin). Increases in FP recall among HT users 60 years and older was maintained for initiators, continuers, opposed, and unopposed (estrogen only). Increases in FP recall among HT users were for imaging and ultrasound but not invasive procedures. Costs for current HT users during the 12 months after screening were not higher than nonusers, except for pharmacy and outpatient mental health. CONCLUSION: The relationship between HT use and FP recall is greatest among older women and does not result in a differential use of invasive procedures.     

Risk of over-diagnosis of COPD in asymptomatic elderly never-smokers.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has defined stage I chronic obstructive pulmonary disease (COPD) as forced expiratory volume in one second/forced vital capacity (FEV1/FVC)% <70% and a FEV1% predicted of >80%. Stage 2 has been defined as FEV1/FVC <70% and a FEV1% pred of <80%. The authors examined the extent of COPD misdiagnosis using this definition in healthy, never-smoker, asymptomatic adults aged >70 yrs in Bergen, Norway. A respiratory questionnaire was mailed to a random sample of 2,871 persons aged >70 yrs. In a random, well-defined subgroup of 208 never-smoker respondents with no current respiratory disease and significant dyspnoea or heart disease/hypertension complicated with dyspnoea, 71 were able to perform an acceptable spirometry. Approximately 35% of these healthy, elderly never-smokers had an FEV1/FVC% of <70% and would be classified as having at least a stage 1 COPD. This percentage increased with age and in those aged >80 yrs approximately 50% would be classified as having COPD and approximately one-third would have an FEV1 of <80% pred (stage 2 COPD). The estimated 5th percentile of FEV1 was consistently <80% pred. The Global Initiative for Chronic Obstructive Lung Disease criteria will probably lead to a significant degree of over-diagnosis of chronic obstructive pulmonary disease in those aged >70 yrs. The criteria used to define the various stages of chronic obstructive pulmonary disease need to be age-specific.     

Six-second spirometry for detection of airway obstruction: a population-based study in Austria

RATIONALE: The presence of airway obstruction is currently defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines on the basis of the post-bronchodilator (BD) FEV(1)/FVC. It has been proposed that the traditional FVC can be replaced with the shorter and less demanding FEV(6) for detecting airway obstruction. OBJECTIVES: A comparison of FEV(1)/FVC and FEV(1)/FEV(6) for the detection of airway obstruction in population-based post-bronchodilator spirometry data. METHODS: A population-based sample of 1,349 adults participated in the Burden of Obstructive Lung Disease study in Austria. Specially trained and certified technicians conducted pre-BD and post-BD spirometry according to American Thoracic Society guidelines and administered standardized questionnaires. A total of 93% of the post-BD test sessions were acceptable, and were included in this analysis. The Third National Health and Nutrition Examination Survey reference equations were used to calculate predicted values and lower limits of normal (LLN) for FEV(1), FEV(6), FVC, FEV(1)/FVC, and FEV(1)/FEV(6). MEASUREMENTS AND MAIN RESULTS: The post-BD FEV(1)/FVC was below the LLN in 199 (15.8%) subjects. The sensitivity of the FEV(1)/FEV(6) for airway obstruction depended greatly on the threshold of percent predicted FEV(1) also used in the definition. The overall sensitivity of FEV(1)/FEV(6) for a diagnosis of airway obstruction, as defined by FEV(1)/FVC (including participants with an FEV(1) above the LLN), was 72.9%, with 98.8% specificity. The sensitivity increased to 98.0% when a low FEV(1) was also required to diagnose post-BD airway obstruction. The discordant cases had long forced expiratory times, often showed a flow-volume curve pattern consistent with two-compartment emptying, and were more often never-smokers. CONCLUSIONS: Six-second spirometry maneuvers (which measure FEV(6)) are as sensitive and specific for post-BD airway obstruction as traditional (prolonged exhalation time) FVC maneuvers only when the definition of airway obstruction includes a low FEV(1).     

A pooled analysis of FEV1 decline in COPD patients randomized to inhaled corticosteroids or placebo

BACKGROUND: There is controversy about whether therapy with inhaled corticosteroids (ICSs) modifies the natural history of COPD, characterized by an accelerated decline in FEV(1). METHODS: The Inhaled Steroids Effect Evaluation in COPD (ISEEC) study is a pooled study of patient-level data from seven long-term randomized controlled trials of ICS vs placebo lasting >/= 12 months in patients with moderate-to-severe COPD. We have previously reported a survival benefit for ICS therapy in COPD patients using ISEEC data. We aimed to determine whether the regular use of ICSs vs placebo improves FEV(1) decline in COPD patients, and whether this relationship is modified by gender and smoking. RESULTS: There were 3,911 randomized participants (29.2% female) in this analysis. In the first 6 months after randomization, ICS use was associated with a significant mean (+/- SE) relative increase in FEV(1) of 2.42 +/- 0.19% compared with placebo (p < 0.01), which is quantifiable in absolute terms as 42 mL in men and 29 mL in women over 6 months. From 6 to 36 months, there was no significant difference between placebo and ICS therapy in terms of FEV(1) decline (-0.01 +/- 0.09%; p = 0.86). The initial treatment effect was dependent on smoking status and gender. Smokers who continued to smoke had a smaller increase in FEV(1) during the first 6 months than did ex-smokers. Female ex-smokers had a larger increase in FEV(1) with ICS therapy than did male ex-smokers. CONCLUSIONS: We conclude that in COPD in the first 6 months of treatment, ICS therapy is more effective in ex-smokers than in current smokers with COPD in improving lung function, and women may have a bigger response to ICSs than men. However, it seems that after 6 months, ICS therapy does not modify the decline in FEV(1) among those who completed these randomized clinical trials.     

COPD exacerbations: the importance of a standard definition

Efforts to assess the efficacy of new therapies in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) have been hampered by the lack of a widely agreed and consistently used definition. A variety of definitions have been used in clinical studies, based on changes in patient symptoms or the requirement for antibiotic therapy, oral steroids or hospitalisation. To date, none of these definitions have been assessed in detail for their reliability, responsiveness and validity determined. Considerable heterogeneity in the aetiology and manifestation of COPD exacerbations makes identification and quantification of defining symptoms extremely difficult. New approaches are therefore being sought with a view to identifying a serum or tissue marker that can be used as a valuable diagnostic tool. Improvements in data recording will also contribute to the accuracy of data retrieval and assessment. If we are to progress to a level of sophistication seen in the diagnosis and management of other diseases, it is evident that considerable research efforts will be required to improve our understanding of COPD exacerbations and develop a standard definition for these events, thereby facilitating the assessment of therapeutic approaches.     

Incidence of Churg-Strauss syndrome in asthma drug users: a population-based perspective

OBJECTIVE: To estimate the incidence of Churg-Strauss syndrome (CSS) among a large population of asthma drug users. METHODS: A retrospective study was conducted among patients who had been dispensed asthma drugs at 3 managed care organizations. Adults who received >or =3 dispensings of an asthma drug during any consecutive 12-month period between January 1, 1995 and June 30, 2000 were identified. Information on patient age, gender, enrollment status, asthma drugs dispensed, and inpatient and outpatient diagnoses and procedures was obtained from automated databases. Chart reviews were performed on persons identified by combinations of diagnostic and billing codes indicative of CSS. A rheumatologist reviewed abstracted information on all subjects; those who met >or =2 American College of Rheumatology criteria for CSS were reviewed by 2 clinical experts. Each clinical expert independently rated the cases; disagreements were resolved by consensus. Cases classified as having "probable/definite" CSS were included in these analyses. The incidence of CSS was estimated overall and according to patient gender, age, and calendar year. RESULTS: From a population of 184,667 asthma drug users contributing 606,184 person-years of exposure, 21 incident cases of CSS were identified (overall incidence of 34.6 per million person-years; 95% confidence interval 21.4 to 53.0). Incidence rates did not differ by gender and age group. The incidence rates for 1995, 1996, 1997, 1998, 1999, and the first 6 months of 2000 were 0, 22, 52, 75, 14, and 14 per million person-years respectively. CONCLUSIONS: Results from this population-based study suggest a somewhat lower incidence of CSS in asthma drug users than previously reported and provides important information as to the risk of developing CSS from a population-based perspective.     

Impact of regular inhaled corticosteroid use on chronic obstructive pulmonary disease outcomes

Inhaled corticosteroids are often used to manage chronic obstructive pulmonary disease, although the evidence regarding their long-term efficacy in preventing or reducing adverse health outcomes is not definitive. This retrospective cohort study analyzed whether regular inhaled corticosteroid use is associated with reduced health care utilization and all-cause mortality related to chronic obstructive pulmonary disease. Subjects were 2,902 health maintenance organization members aged 50 and over who met criteria for chronic obstructive pulmonary disease. The study used a composite endpoint of time to (1) death or (2) hospitalization or emergency room care related to chronic obstructive pulmonary disease, whichever occurred first, during a 4-year follow-up. Among the 42% of chronic obstructive pulmonary disease patients with an indication of co-morbid asthma, inhaled corticosteroid use was associated with significantly reduced risk for both all-cause mortality and the composite outcome. The reduction in risk was greatest in never- and ex-smokers. Among chronic obstructive pulmonary disease patients with no indication of asthma, inhaled corticosteroid use was associated with reduced risk only in never smokers. These findings generally persisted in separate analyses stratified by asthma status and in sensitivity analyses using four alternative definitions of regular medication use, with comparable results when regular medication use was treated as a fixed covariate defined at the start of follow-up. We conclude that use of inhaled corticosteroids was associated with reduced risk of chronic obstructive pulmonary disease exacerbations and all-cause mortality. This benefit was most pronounced among never-smokers and in those with evidence of co-morbid asthma.     

Isolation of intestinal spirochaetes from homosexuals

Spirochaetes were isolated from rectal swabs of two homosexuals and the faeces of a third, using simple isolation techniques not previously applied to specimens of this type. The ease of culture of these organisms will enable their distribution and pathogenicity to be studied, particularly in relation to their significance in homosexuals.     

Dietary vitamin C intake is inversely related to cough and wheeze in young smokers

We aimed to investigate whether dietary vitamin C intake, an important antioxidant, is inversely related to self-reported respiratory symptoms in young adults of a community. A random sample of 4300 subjects, aged 20-44 years, living in Bergen, Norway, received a postal questionnaire on respiratory symptoms; 80% responded. Vitamin C intake (mg per week) was estimated from a food-frequency questionnaire asking how often the subject, during the last year, had consumed units of orange juice, oranges, potatoes, carrots and tomatoes. Significant differences in the intake of vitamin C were observed across smoking categories with current smokers having the lowest intake, while there was no variation by gender, age or occupational dust exposure. Dietary vitamin C intake was in univariate analyses inversely related to "morning cough", "chronic cough", "wheeze" and "wheeze ever". After adjusting for gender, age, body mass index, "occupational exposure" pack-years as well as having and stratified on smoking habits in multiple logistic regression analyses, the relationship between dietary vitamin C intake and "cough" and "wheeze" tended to be associated to smoking. The odds ratio (OR) for "morning cough" was 0.68 (95% CI: 0.35-0.95), "chronic cough" OR 0.69 (95% CI: 0.47-1.04) and "wheeze ever" OR 0.75 (95% CI: 0.56-1.01) in current-smokers with dietary vitamin C intake in the upper (> or =395 mg/ week) vs. the lower (<209 mg/week) tertile. The OR for "wheeze" was 0.56 (95% CI: 0.35-0.88) in ex-smokers. The magnitude ofthese effects remained after excluding subjects with supplementary vitamin C intake (n=199) from the statistical analyses. Among young Norwegian adults, having a low prevalence of asthma and high prevalences of smoking-related respiratory symptoms, dietary vitamin C intake may act as an antioxidant and thereby reduce cough and wheeze in smokers having high oxidant stress.