Longitudinal development of initial, chronic and mucoid Pseudomonas aeruginosa infection in young children with cystic fibrosis.

BACKGROUND: While the emergence of chronic and mucoid Pseudomonas aeruginosa (Pa) infection are both associated with poorer outcomes among CF patients, their relationship is poorly understood. We examined the longitudinal relationship of incident, chronic and mucoid Pa in a contemporary, young CF cohort in the current era of Pa eradication therapy. METHODS: This retrospective cohort was comprised of patients in the U.S. CF Foundation Patient Registry born 2006-2015, diagnosed before age 2, and with at least 3 respiratory cultures annually. Incidence and age-specific prevalence of Pa infection stages (initial and chronic [≥ 3Pa+cultures in prior year]) and of mucoid Pa were summarized. Transition times and the interaction between Pa stage and acquisition of mucoid Pa were examined via Cox models. RESULTS: Among the 5592 CF patients in the cohort followed to a mean age of 5.5years, 64% (n=3580) acquired Pa. Of those, 13% (n=455) developed chronic Pa and 17% (n=594) cultured mucoid Pa. Among those with mucoid Pa, 36% (211/594) had it on their first recorded Pa+culture, while mucoid Pa emerged at or after entering the chronic stage in 12% (73/594). Mucoidy was associated with significantly increased risk of transition to chronic Pa infection (HR=2.59, 95% CI 2.11, 3.19). CONCLUSIONS: Two-thirds of early-diagnosed young children with CF acquired Pa during a median 5.6years of follow up, among whom 13% developed chronic Pa and 17% acquired mucoid Pa. Contrary to our hypothesis, 87% of young children who developed mucoid Pa did so before becoming chronically infected.

Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator gene. Recombinant adenoviruses have shown promise as vectors for transfer of CF transmembrane conductance regulator cDNA to airway epithelia and correction of the Cl- transport defect. However, because adenovirus-mediated gene transfer is transient, use of adenovirus as a vector for treatment of CF would require repeated administration. Therefore, we evaluated repeat administration of an adenovirus vector to the nasal epithelium of patients with CF with five escalating doses of up to 10(10) infectious units. There were no detectable adverse affects. All subjects were initially seropositive but developed additional humoral immune responses. The vector partially corrected the defect in airway epithelial Cl- transport in some subjects, although there was variability between subjects and there was less correction with subsequent administration, perhaps because the immune response limited gene transfer. Future work must focus on vectors with increased efficiency and with the ability to evade host defenses.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis.

BACKGROUND: Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS: Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS: The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS: Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Long-term mortality study of oil refinery workers. IV. Exposure to the lubricating-dewaxing process.

A retrospective cohort mortality study of 1,008 male oil refinery workers who ever worked on the lubricating-dewaxing process of the lube oil department and who have been followed for a period of 43 years is presented. These workers were exposed to a number of solvents, primarily methyl ethyl ketone [(MEK) CAS: 78-93-3] and toluene (CAS: 108-88-3), but at levels far below the current Occupational Safety and Health Administration's standard. The standardized mortality ratio (SMR) for all causes (0.70) and the SMR for cancer (0.86) are much lower than unity when they are compared to the mortality experience of the U.S. population. Also observed in this study were 8 prostate cancer deaths (4.4 expected) with an SMR of 1.82, which was not statistically significant (P = .16). Seven of these 8 prostate cancer deaths occurred among nonwhite males, who showed an SMR of 2.47 (P = 0.53). However, only 1 prostate cancer death was seen among workers specifically assigned to the MEK units. The remaining deaths occurred among maintenance workers who had lube oil department-wide assignments. This cancer risk increased with increasing duration of employment in the lube oil department. A latency of 20 years or more was also observed for these prostate cancer deaths. In this study the processing of lubricating oils was found to be at least as important as the MEK solvents, and department-wide maintenance workers were as much at risk as the MEK unit workers. In view of this finding and findings obtained by others, it seems prudent to continue to study lubricating-dewaxing process workers, including the medical monitoring of all such workers for prostate cancer.

Dental implantology education: a survey of opinion and experience of 106 general dental practitioners.

In the United Kingdom the National Health Service only provides dental implant treatment to patients who fulfil stringent clinical criteria outlined by the Royal College of Surgeons. Such treatment is normally in a hospital setting. The majority of dental implant work is otherwise carried out in the private sector. Concern about the quality of implant dentistry and training led the General Dental Council to convene a working group that set out to set training standards in implant dentistry for general dental practitioners (GDPs). The Faculty of General Dental Practitioners published this guidance in March 2006. This questionnaire based study set out to examine GDP attitudes to implant treatment and training and aims to contribute to the debate and review of appropriate training in dental implantology for GDPs.

Varicella outbreaks in Army recruits from Puerto Rico. Varicella susceptibility in a population from the tropics.

Two outbreaks of varicella consisting of a total of 105 cases occurred in a highly varicella-susceptible population of young adult Army recruits from Puerto Rico enrolled in the Defense Language Institute in San Antonio, Tex, between October 1986 and November 1987. Epidemiologic investigation found a significantly higher risk for enlisted recruits housed in open barracks than for officers housed in private rooms. The attack rate in the first outbreak was 30%, with an estimated attack rate of 71% among susceptible persons. Serologic testing of 810 adult recruits from Puerto Rico for varicella-zoster antibody by means of an enzyme-linked immunosorbent assay procedure found 42% to be seronegative, with no significant difference by sex. The enzyme-linked immunosorbent assay test had a positive predictive value for absence of disease development of 95% in the second outbreak. Serologic test results were successfully used as part of the outbreak control strategy, with a resultant decrease in attack rates to 19% overall and 30% among susceptible persons in the second outbreak. Uniquely susceptible adult populations placed in conditions with high likelihood of infection on exposure are potential candidates for the varicella vaccine after its licensure.

A phase I study of aerosolized administration of tgAAVCF to cystic fibrosis subjects with mild lung disease.

Cystic fibrosis (CF) is one of the most common autosomal recessive disorders in North America, leading to significant morbidity and early mortality. The defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) function can be corrected in vitro by gene replacement with a wild-type gene. A Phase I, single administration, dose escalation trial was designed and executed to assess safety and delivery of tgAAVCF, an adeno-associated virus (AAV) vector encoding the human CFTR cDNA, by nebulization to the lungs of CF subjects. Four cohorts of three subjects each were administered increasing doses of the study agent, beginning with 10(10) DNase-resistant particles (DRP) and escalating in log increments up to 10(13) DRP. Sequential bronchoscopies were performed to gather analytical samples throughout the study. All 12 subjects completed the study. There were a total of 242 adverse events (AEs), six of which were defined as serious and three of which were defined as possibly being related to the study drug. A clear dose-response relationship was observed in vector gene transfer. A maximum of 0.6 and 0.1 vector copies per brushed cell were observed 14 days and 30 days, respectively, following nebulization of 10(13) DRP tgAAVCF, and this declined to nearly undetectable levels by day 90. Vector gene transfer was evenly distributed throughout the fourth airway generation following single-dose administration. RNA-specific PCR did not detect vector-derived mRNA. This Phase I trial shows that aerosolized tgAAVCF is safe and widely delivered to the proximal airways of CF subjects by nebulization.

Role of endothelial nitric oxide synthase in estrogen-induced osteogenesis.

It is well recognized that high-dose estrogen induces a marked osteogenic response in long bones of female mice. In light of evidence which suggests that nitric oxide synthase (NOS) plays a role in regulation of osteoblast activity, we analyzed whether NOS is involved in mediating this response. Intact female mice were administered 17beta-estradiol (E(2)) either alone or in combination with N(G)-nitro-L-arginine methylester (L-NAME) or aminoguanidine (AG), over 24 days. The former inhibits both constitutive and inducible isoforms of NOS, whereas the latter is a selective inhibitor of inducible NOS. Bone mineral density (BMD) of the femur was subsequently measured by dual-energy X-ray absorptiometry (DXA), and histomorphometry performed at the proximal metaphysis on longitudinal tibial sections. As expected, E(2) given alone led to a marked accumulation of cancellous bone at the proximal tibial metaphysis, associated with a significant gain in femoral BMD, and an increase in cancellous mineralizing surfaces as assessed by histomorphometry. Neither L-NAME nor AG affected cancellous histomorphometric indices when given alone. However, when administered in combination with L-NAME, the magnitude of the skeletal response to E(2) was significantly reduced. The tendency for L-NAME to reduce estrogen-induced bone formation within the proximal tibial metaphysis was more marked distally compared with proximally. In contrast, AG showed no tendency to suppress the osteogenic response to E(2). Subsequently, we examined the effect of E(2) administration on expression within mouse femoral bone marrow of endothelial NOS (eNOS), which is the predominant constitutive isoform of NOS within bone. No change in eNOS mRNA levels was observed following E(2) administration, as assessed by reverse transcription-polymerase chain reaction (RT-PCR). Taken together, our results suggest that eNOS plays a role in mediating estrogen-induced bone formation in intact female mice, possibly as a consequence of posttranscriptional regulation of eNOS activity by estrogen.

Diaphragmatic failure during group B streptococcal sepsis in piglets: the role of thromboxane A2.

Group B Streptococcus (GBS) causes an impairment of diaphragmatic pressure generation (Pdi) in 2-wk-old piglets, whereas 4-wk-old piglets are unaffected. In this study, we examined the effect on 4-wk-old piglets of a higher dose of GBS than previously utilized. We sought to determine whether an eicosanoid product of arachidonic acid metabolism accounted for the decrease in Pdi during GBS infusion and whether thromboxane A2 (TxA2) is the putative eicosanoid mediator of decreased Pdi during GBS infusion. Measuring Pdi during phrenic nerve stimulation, we studied four groups of anesthetized spontaneously breathing 4-wk-old piglets. Group 1 (GBS) was infused with live GBS, which caused a decrease in Pdi by 1 h at 20-, 30-, 50-, and 100-Hz stimulation frequencies. Group 2 [GBS + indomethacin (Indo)] was pretreated with Indo before GBS infusion. In the GBS + Indo group, Pdi did not decrease throughout 4 h of GBS infusion. Because Indo proved to be protective of Pdi during GBS infusion, we examined the role of TxA2, the only eicosanoid present at 1 h in the serum of GBS-infused piglets. Group 3 was infused with the TxA2 analogue U-46619 only for 1 h. Group 4 was treated with the TxA2-receptor antagonist SQ-29548 before and concomitant with GBS infusion for 1 h; the SQ-29548 was then discontinued, and GBS was continued for 1 h more. In the U-46619-infused group, Pdi decreased at 1 h, and in the SQ-29548-treated group, Pdi did not decrease during GBS infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of amrinone during group B Streptococcus-induced pulmonary hypertension in piglets.

Intravenous infusion of group B Streptococcus (GBS) into neonatal animals produces pulmonary hypertension, ventilation/perfusion (VA/Q) mismatch, and an increase in serum levels of thromboxane B2 (TxB2) and tumor necrosis factor (TNF) alpha. The vasodilator amrinone (amr) is a cGMP-inhibited phosphodiesterase inhibitor and is reported to inhibit thromboxane A2 and TNF production. We hypothesized that infusion of amr would cause pulmonary vasodilation and reduce serum TxB2 and TNF levels in piglets with late phase GBS-induced pulmonary hypertension. The effect of amr on gas exchange was also determined. A continuous infusion of GBS was administered for 5 hr to 4 groups of anesthetized, mechanically ventilated neonatal piglets. An amr bolus of 8 mg/kg was given at 4 hr followed by a 1 hr continuous infusion of either 10 or 20 micrograms/kg/min of amr (amr 10 and amr 20, respectively). Control piglets received a bolus and 1 hr infusion of amr carrier. The infusion of amr, but not of carrier reversed late phase GBS-induced pulmonary hypertension. Piglets infused with amr 20 showed transient selective pulmonary vasodilation, based on a reduced ratio of pulmonary to systemic vascular resistance (PVR/SVR ratio) value at 30 min but not at 1 hr, compared to pre-amr treatment values. The PVR/SVR ratio values for amr 10 and control group did not change after treatment with either amr or carrier. Treatment with amr 10 or 20 did not decrease serum TxB2 or TNF levels or increase VA/Q mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory mechanics of the piglet during the first month of life.

Piglets at 3, 14, and 30 days of age were studied to assess the postnatal changes in lung, chestwall, and total respiratory system compliance associated with normal growth. Static deflation compliance of the lung and total respiratory system increased significantly with age; there was no change in chestwall compliance. When normalized for body weight or lung volume, all measures of compliance tended to decrease with postnatal age. Measures of lung and chestwall compliance obtained with an end-inspiratory occlusion technique were less than the static compliance measures, but demonstrated the same relative changes with postnatal maturation. Chestwall compliance at 3 days of age was only 1.3 times greater than lung compliance and there was no significant change in this ratio with postnatal age. In contrast to the trend for the human infant, the piglet's chestwall at 3 days of age is stiff relative to the lung and does not become stiffer with age over the first 4 weeks of life.

Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis.

A thorough understanding of the early natural history of cystic fibrosis (CF) lung disease is critical for the development of effective interventions in the youngest patients. We assessed the evolution of pulmonary infection, inflammation, and clinical course among 40 infants over a 2-year period through annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semiannual infant pulmonary function testing, and quarterly clinical evaluations. Both the prevalence of CF pathogens and their density in BAL fluid increased with age. Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered. Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P. aeruginosa or another pathogen. IL-10 concentrations were similar in CF subjects and non-CF historical controls. Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping). Subjects from whom CF pathogens were isolated at > 10(5) cfu/mL had the worst air trapping and lowest Brasfield chest X-ray scores. Our findings provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy.

The role of group B streptococci beta-hemolysin expression in newborn lung injury.

There is a direct correlation between the level of GBS beta-hemolysin expression and the ability of GBS to injury lung epithelial cells. Electron microscopy suggest the hemolysin acts as a pore-forming cytolysin. beta-hemolysin-associated lung epithelial cell injury is inhibited by surfactant phospholipid, a substance in which high-risk premature infants are deficient. We have now shown that loss of GBS hemolysin activity is associated with decreased animal virulence following intrathoracic inoculation of the organism. Further, a knockout of a putative GBS beta-hemolysin gene from the literature suggests it is not the major GBS hemolysin determinant. Cloning and sequencing analysis of the Tn916 (or Tn916DE) insertions in three of our nonhemolytic GBS mutants show identical integration sites in a distinct chromosomal locus. Finally, a putative 11-kd hemolysin species is identified by comparative analysis of protein extracts from isogenic hemolysin mutants.

Childhood sexual abuse and adult loneliness and network orientation.

Women who are sexually abused may be at greater risk for loneliness and less likely to utilize their social support system. Data regarding a history of sexual abuse, and network orientation were gathered from 231 female university students, 24 of whom indicated a history of abuse, and from 26 female clients at two treatment centers. Victims of sexual abuse were found to be more lonely and less likely to utilize their social support system than the controls. Contrary to expectations, those who were in treatment were more lonely and less likely to use social support than those not in treatment. Those in treatment were also victims for a longer period of time involving more incidents than those not in treatment. One-way ANOVA's found the treatment group more lonely than the nontreatment and control groups who did not differ from each other; however, on network orientation all groups differed from each other in the expected direction. These findings support reports that victims of sexual abuse tend to isolate themselves from others.

Irritable bowel syndrome: overview of diagnosis and treatment.

Irritable bowel syndrome (IBS) is common in primary care practice and in gastroenterology clinics and is occasionally seen in psychiatric clinics. The symptoms include abdominal cramping, bloating, and pain, as well as diarrhea, constipation, or both. Treatment includes patient education and reassurance, dietary modification, medications if necessary, and consideration of psychological interventions. The etiology of IBS is poorly understood. Research suggests a role for bowel dysmotility, altered pain perception, history of physical and sexual abuse, and psychiatric disturbance, though none of these factors alone has been proven to cause IBS.

Aztreonam for inhalation solution (AZLI) in patients with cystic fibrosis, mild lung impairment, and P. aeruginosa.

BACKGROUND: Previous aztreonam for inhalation solution (AZLI) studies included patients with cystic fibrosis, Pseudomonas aeruginosa (PA) airway infection, and forced expiratory volume in 1s (FEV(1)) 25% to 75% predicted. This double-blind, multicenter, randomized, placebo-controlled trial enrolled patients (≥6 years) with FEV(1)>75% predicted. METHODS: AZLI 75 mg (n=76) or placebo (n=81) was administered 3-times daily for 28days with a 14-day follow-up. RESULTS: Day 28 treatment effects were 1.8points for CFQ-R-Respiratory Symptoms Scale (95%CI: -2.8, 6.4; p=0.443; primary endpoint); -1.2 for log(10) sputum PA colony-forming units (p=0.016; favoring AZLI), and 2.7% for relative FEV(1)% predicted (p=0.021; favoring AZLI). Treatment effects favoring AZLI were larger for patients with baseline FEV(1) <90% predicted compared to ≥90% predicted. AZLI was well-tolerated. CONCLUSIONS: Effects on respiratory symptoms were modest; however, FEV(1) improvements and bacterial density reductions support a possible role for AZLI in these relatively healthy patients.

Occupational medicine in the eighties: decade of change.

This chapter focuses on current medical practices in the petroleum industry as they reflect the social, managerial, technological and regulatory changes of the present decade. Modern health policies and medical organizations are reviewed, with emphasis on health evaluation programs, health information distribution and clinical services. The author concludes with commentary about apparent future trends.

Group B streptococcal beta-hemolysin promotes injury of lung microvascular endothelial cells.

Group B streptococci (GBS) are the leading cause of pneumonia and sepsis in human newborns. Exudative pulmonary edema and alveolar hemorrhage seen in GBS pneumonia indicate vascular damage, and we reported that GBS injure lung microvascular endothelial cells (LMvEC) both in vivo and in vitro. The specific GBS factors causing LMvEC injury are uncertain, but GBS beta-hemolysin activity is associated with lung epithelial cell injury. We hypothesized that GBS beta-hemolysin contributes to LMvEC injury and exudative pulmonary edema. To test this hypothesis we used isogenic nonhemolytic and hyperhemolytic GBS mutants derived by transposon insertional mutagenesis from three different wild-type strains. Hemolytic titers for each strain were calculated using live GBS and Tween 80/starch-stabilized extracts of log-phase GBS. All nonhemolytic mutants lacked detectable hemolytic activity, whereas hyperhemolytic mutants produced 4-16 times the hemolytic activity of their parent strains. LMvEC injury was assayed by light microscopy, the release of lactate dehydrogenase, trypan blue nuclear staining and Evans blue-albumin flux. Compared with the parent strains, all nonhemolytic mutants caused significantly reduced, and all hyperhemolytic mutants caused significantly greater lactate dehydrogenase release from and trypan blue nuclear staining of LMvEC. Moreover, a nonhemolytic mutant caused reduced and a hyperhemolytic mutant caused increased Evans-blue albumin flux across polar LMvEC monolayers. These findings were corroborated by light microscopic evidence of hemolysin-associated damage to the LMvEC monolayers. We conclude that GBS beta-hemolysin promotes LMvEC injury and increases permeability in vitro, and speculate that GBS beta-hemolysin contributes to the pathogenesis of alveolar edema and hemorrhage in early onset GBS pneumonia.