Lung cancer: Premalignant biology and medical prevention.

Lung cancer (both adenocarcinoma and squamous cell) progress through a series of pre-malignant histologic changes before the development of invasive disease. Each of these carcinogenic cascades is defined by genetic and epigenetic alterations in pulmonary epithelial cells. Additionally, alterations in the immune response, progenitor cell function, mutational burden, and microenvironmental mediated survival of mutated clones contribute to the risk of pre-malignant lesions progressing to cancer. Medical preventions studies have been completed and current and future trials are informed by the improved understanding of pre-malignancy. This will lead to precision chemoprevention trials based on lesional biology and histologic characteristics.

Providing supplemental milk to piglets preweaning improves the growth but not survival of gilt progeny compared with sow progeny.

Gilt progeny have lighter weaning weights and greater postweaning medication and mortality rates compared with the progeny of older parity sows. Because weaning weight has been positively correlated with postweaning survival, this study aimed to determine whether the provision of supplemental milk preweaning could improve weaning weight and subsequent weights as well as postweaning survival of gilt progeny. The study was replicated in summer and winter as the effects of supplemental milk were expected to vary with season. The progeny of 80 gilts (parity 0) and 80 sows (parity 2 to 5) were allocated to both treatments: with or without supplemental milk in these 2 seasons with 5 sheds/season. Litter size was standardized (10 to 11 piglets) and each piglet was weighed at birth, d 21, weaning (4 wk), and 10 wk of age. Medications and mortalities were recorded both preweaning and postweaning. Pigs were housed within treatment groups postweaning, and ADFI and G:F were measured. Gilt progeny were 200 g lighter at birth in both replicates (P < 0.001) and were 500 g lighter at weaning in the winter replicate (P < 0.05) compared with sow progeny. The provision of supplemental milk improved weaning weight for both gilt and sow progeny by 800 g in summer (P < 0.05) and by 350 g in winter (P < 0.05). This improvement in weaning weight had no effect on the incidence of death or disease in milk-supplemented progeny of either gilts or sows (P > 0.05). Supplemental milk disappearance (the daily difference between the volume of milk provided and the residue left in the drinker) was greater in summer than winter (by 130 mL/piglet d(-1); P < 0.05) as were the associated weaning weight benefits. The weaning weights of supplemented gilt progeny reached or exceeded that of nonsupplemented sow progeny. Gilt progeny had greater postweaning mortality (2.6%) and medication rates (6.2%) than sow progeny (1 and 2.2%, respectively; both P < 0.05) in both seasons, but medication rates were greater in winter (7.2%) for both treatment groups than in summer (1.9%; P < 0.05). Gilt progeny also had less postweaning ADFI than sow progeny in winter (528 and 636 g, respectively; P < 0.05) with no dam parity effect on G:F (both P > 0.05). The hypothesis that supplemental milk provision did increase gilt progeny weaning weight was supported (especially in summer) but the supplementation had no effect on postweaning weights and survival. Efforts to improve gilt progeny postweaning growth and survival need to be aimed at improving health and immunity, not just weaning weight.

Postpartum diet quality in Australian women following a gestational diabetes pregnancy.

BACKGROUND/OBJECTIVES: To describe the diet quality of a national sample of Australian women with a recent history of gestational diabetes mellitus (GDM) and determine factors associated with adherence to national dietary recommendations. SUBJECTS/METHODS: A postpartum lifestyle survey with 1499 Australian women diagnosed with GDM ≤3 years previously. Diet quality was measured using the Australian recommended food score (ARFS) and weighted by demographic and diabetes management characteristics. Multinominal logistic regression analysis was used to determine the association between diet quality and demographic characteristics, health seeking behaviours and diabetes-related risk factors. RESULTS: Mean (±s.d.) ARFS was 30.9±8.1 from a possible maximum score of 74. Subscale component scores demonstrated that the nuts/legumes, grains and fruits were the most poorly scored. Factors associated with being in the highest compared with the lowest ARFS quintile included age (odds ratio (OR) 5-year increase=1.40; 95% (confidence interval) CI:1.16-1.68), tertiary education (OR=2.19; 95% CI:1.52-3.17), speaking only English (OR=1.92; 95% CI:1.19-3.08), being sufficiently physically active (OR=2.11; 95% CI:1.46-3.05), returning for postpartum blood glucose testing (OR=1.75; 95% CI:1.23-2.50) and receiving risk reduction advice from a health professional (OR=1.80; 95% CI:1.24-2.60). CONCLUSIONS: Despite an increased risk of type 2 diabetes, women in this study had an overall poor diet quality as measured by the ARFS. Women with GDM should be targeted for interventions aimed at achieving a postpartum diet consistent with the guidelines for chronic disease prevention. Encouraging women to return for follow-up and providing risk reduction advice may be positive initial steps to improve diet quality, but additional strategies need to be identified.

A preliminary study of the effects of Tai Chi and Qigong medical exercise on indicators of metabolic syndrome, glycaemic control, health-related quality of life, and psychological health in adults with elevated blood glucose.

OBJECTIVES: To evaluate the feasibility, acceptability and effects of a Tai Chi and Qigong exercise programme in adults with elevated blood glucose. DESIGN, SETTING, AND PARTICIPANTS: A single group pre-post feasibility trial with 11 participants (3 male and 8 female; aged 42-65 years) with elevated blood glucose. INTERVENTION: Participants attended Tai Chi and Qigong exercise training for 1 to 1.5 h, 3 times per week for 12 weeks, and were encouraged to practise the exercises at home. MAIN OUTCOME MEASURES: Indicators of metabolic syndrome (body mass index (BMI), waist circumference, blood pressure, fasting blood glucose, triglycerides, HDL-cholesterol); glucose control (HbA1c, fasting insulin and insulin resistance (HOMA)); health-related quality of life; stress and depressive symptoms. RESULTS: There was good adherence and high acceptability. There were significant improvements in four of the seven indicators of metabolic syndrome including BMI (mean difference -1.05, p<0.001), waist circumference (-2.80 cm, p<0.05), and systolic (-11.64 mm Hg, p<0.01) and diastolic blood pressure (-9.73 mm Hg, p<0.001), as well as in HbA1c (-0.32%, p<0.01), insulin resistance (-0.53, p<0.05), stress (-2.27, p<0.05), depressive symptoms (-3.60, p<0.05), and the SF-36 mental health summary score (5.13, p<0.05) and subscales for general health (19.00, p<0.01), mental health (10.55, p<0.01) and vitality (23.18, p<0.05). CONCLUSIONS: The programme was feasible and acceptable and participants showed improvements in metabolic and psychological variables. A larger controlled trial is now needed to confirm these promising preliminary results.

Tumour necrosis factor gene polymorphisms are associated with COPD.

Tumour necrosis factor (TNF)-alpha has been shown to be an important factor in animal models of chronic obstructive pulmonary disease (COPD). However, human studies of TNF polymorphisms in COPD have been equivocal. Six TNF single nucleotide polymorphisms (-1031C/T, -863C/A, -857C/T, -237G/A, -308G/A and +487G/A) and their haplotypes were investigated in 423 Caucasian smokers (298 patients with spirometric evidence of COPD and 125 without airflow obstruction). The -308 minor allele (A) had a higher odds ratio (OR) of being associated with COPD in multivariate analysis (controlling for age, sex, pack-yrs; OR 1.9, 95% confidence interval (CI) 1.1-3.2) and was also associated with worse forced expiratory volume in one second/forced vital capacity. The -237 minor allele (A) had a lower OR of being associated with COPD (OR 0.40, 95% CI 0.19-0.86). In COPD patients, the -857 minor allele (T) had a lower OR of being associated with severe stages of COPD (Global Initiative for Obstructive Lung Disease stage III and IV versus stage I and II, OR 0.46, 95% CI 0.24-0.88). Other TNF single nucleotide polymorphisms were not associated with COPD but the -1031/-863 haplotype CC/TC had a lower OR in COPD patients versus smoking controls (OR 0.22, 95% CI 0.05-0.97). The present study adds further evidence that tumour necrosis factor genotypes play a role in susceptibility to cigarette smoke.

New experimental and theoretical approach to the heterogeneous hydrolysis of NO2: key role of molecular nitric acid and its complexes.

Although heterogeneous chemistry on surfaces in the troposphere is known to be important, there are currently only a few techniques available for studying the nature of surface-adsorbed species as well as their chemistry and photochemistry under atmospheric conditions of 1 atm pressure and in the presence of water vapor. We report here a new laboratory approach using a combination of long path Fourier transform infrared spectroscopy (FTIR) and attenuated total reflectance (ATR) FTIR that allows the simultaneous observation and measurement of gases and surface species. Theory is used to identify the surface-adsorbed intermediates and products, and to estimate their relative concentrations. At intermediate relative humidities typical of the tropospheric boundary layer, the nitric acid formed during NO2 heterogeneous hydrolysis is shown to exist both as nitrate ions from the dissociation of nitric acid formed on the surface and as molecular nitric acid. In both cases, the ions and HNO3 are complexed to water molecules. Upon pumping, water is selectively removed, shifting the NO(3-)-HNO3(H2O)y equilibria toward more dehydrated forms of HNO3 and ultimately to nitric acid dimers. Irradiation of the nitric acid-water film using 300-400 nm radiation generates gaseous NO, while irradiation at 254 nm generates both NO and HONO, resulting in conversion of surface-adsorbed nitrogen oxides into photochemically active NO(x). These studies suggest that the assumption that deposition or formation of nitric acid provides a permanent removal mechanism from the atmosphere may not be correct. Furthermore, a potential role of surface-adsorbed nitric acid and other species formed during the heterogeneous hydrolysis of NO2 in the oxidation of organics on surfaces, and in the generation of gas-phase HONO on local to global scales, should be considered.

Photochemical processes induced by vibrational overtone excitations: dynamics simulations for cis-HONO, trans-HONO, HNO3, and HNO3-H2O.

Photochemical processes in HNO3, HNO3-H2O, and cis- and trans-HONO following overtone excitation of the OH stretching mode are studied by classical trajectory simulations. Initial conditions for the trajectories are sampled according to the initially prepared vibrational wave function. Semiempirical potential energy surfaces are used in "on-the-fly" simulations. Several tests indicate at least semiquantitative validity of the potential surfaces employed. A number of interesting new processes and intermediate species are found. The main results include the following: (1) In excitation of HNO3 to the fifth and sixth OH-stretch overtone, hopping of the H atom between the oxygen atoms is found to take place in nearly all trajectories, and can persist for many picoseconds. H-atom hopping events have a higher yield and a faster time scale than the photodissociation of HNO3 into OH and NO2. (2) A fraction of the trajectories for HNO3 show isomerization into HOONO, which in a few cases dissociates into HOO and NO. (3) For high overtone excitation of HONO, isomerization into the weakly bound species HOON is seen in all trajectories, in part of the events as an intermediate step on the way to dissociation into OH + NO. This process has not been reported previously. Well-established processes for HONO, including cis-trans isomerization and H hopping are also observed. (4) Only low overtone levels of HNO3-H2O have sufficiently long liftimes to be spectrocopically relevant. Excitation of these OH stretching overtones is found to result in the dissociation of the cluster H hopping, or dissociation of HNO3 does not take place. The results demonstrate the richness of processes induced by overtone excitation of HNO(x) species, with evidence for new phenomena. Possible relevance of the results to atmospheric processes is discussed.

Ab initio vibrational calculations for H2SO4 and H2SO4 x H2O: spectroscopy and the nature of the anharmonic couplings.

Vibrational frequencies for fundamental, overtone, and combination excitations of sulfuric acid (H2SO4) and of sulfuric acid monohydrate cluster (H2SO4 x H2O) are computed directly from ab initio MP2/TZP potential surface points using the correlation-corrected vibrational self-consistent field (CC-VSCF) method, which includes anharmonic effects. The results are compared with experiment. The computed transitions show in nearly all cases good agreement with experimental data and consistent improvement over the harmonic approximation. The CC-VSCF improvements over the harmonic approximation are largest for the overtone and combination excitations and for the OH stretching fundamental. The agreement between the calculations and experiment also supports the validity of the MP2/TZP potential surfaces. Anharmonic coupling between different vibrational modes is found to significantly affect the vibrational frequencies. Analysis of the mean magnitude of the anharmonic coupling interactions between different pairs of normal modes is carried out. The results suggest possible mechanisms for the internal flow of vibrational energy in H2SO4 and H2SO4 x H2O.

The effectiveness of physical activity interventions for the treatment of overweight and obesity and type 2 diabetes.

This review summarises current evidence relating to the effectiveness of physical activity (PA) interventions for treating overweight and obesity and type 2 diabetes. Interventions to increase PA for the treatment of overweight and obesity in both children and adults have primarily consisted of health education and behaviour modification strategies in clinical settings or with selected families or individuals. Although evidence is limited, strategies to reduce sedentary behaviours appear to have potential for reducing obesity among children and adolescents. Among adults, strategies that combine diet and PA are more effective than PA strategies alone. Combined lifestyle strategies are most successful for maintained weight loss, although most programs are unsuccessful in producing long-term changes. There is little evidence about compliance to prescribed behaviour changes or the factors that promote or hinder compliance to lifestyle changes. Limited evidence suggests that continued professional contact and self-help groups can help sustain weight loss. Most of the interventions for the treatment of type 2 diabetes have been conducted in clinical settings and have typically required the use of extensive resources. Evidence suggests that interventions can lead to small but clinically meaningful improvements in glycaemic control, even in the absence of weight loss. A recent study demonstrated that a multifactorial intervention (diet, PA and pharmaceutical) can reduce the risk of diabetes complications in individuals with type 2 diabetes. Nevertheless, there is little evidence about the effectiveness of community-based interventions in producing long-term changes in glycaemic control and reduced mortality in people with type 2 diabetes.

[Prevalence of psychiatric symptoms and comorbid conditions in 3- to 5-year-old children: results of the Braunschweig Kindergarten Study]. / Häufigkeit psychischer Auffälligkeiten und Begleitsymptome bei drei- bis sechsjährigen Kindern: Ergebnisse der Braunschweiger Kindergartenstudie.

OBJECTIVES: To analyze the frequency of behavioral and emotional problems and comorbidity of kindergarten children in Braunschweig as rated by their parents. METHOD: The analysis is part of the Braunschweiger Kindergartenstudie. In a sample of N = 809 children aged three to six the parents rated their children using a modified version of the Child Behavior Checklist/CBCL 4-18. RESULTS: The prevalence rates range from 0.5% to 5.0%. The most frequent behavioral problems in kindergarten children were aggressive behavior and attention problems, followed by social problems. The study also provides bidirectional comorbidity rates. CONCLUSION: Finally the prevalence rates and the implications of the findings for prevention of behavioral problems in children are discussed.

Sitting time and work patterns as indicators of overweight and obesity in Australian adults.

BACKGROUND: Increasing levels of physical inactivity and sedentariness are contributing to the current overweight and obesity epidemic. In this paper, the findings of two recent studies are used to explore the relationships between sitting time (in transport, work and leisure), physical activity and body mass index (BMI) in two contrasting samples of adult Australians. METHODS: Data on sitting time, physical activity, BMI and a number of demographic characteristics were compared for participants in two studies-529 women who were participants in a preschool health promotion project ('mothers'), and 185 men and women who were involved in a workplace pedometer study ('workers'). Relationships between age, number of children, physical activity, sitting time, BMI, gender and work patterns were explored. Logistic regression was used to predict the likelihood of being overweight or obese, among participants with different physical activity, sitting time and work patterns. RESULTS: The total reported time spent sitting per day (across all domains) was almost 6 h less among the mothers than the workers (P<0.001), and compared with the mothers, a significantly greater proportion of the workers was classified as overweight or obese (BMI > or =25 kg/m(2)). Univariate analysis found that, compared with men in full-time work, women who worked full-time (OR=0.42, CI: 0.24-0.74), part-time (OR=0.35, CI: 0.20-0.59) or in full-time home duties (OR=0.51, CI: 0.29-0.88) were about half as likely to be overweight or obese. Participants who reported high daily levels of sitting (> or =7.4 h) were also significantly more likely than those who reported 'low' levels (<4.7 h/day) to be overweight or obese (OR=1.68, CI: 1.16-2.42). Multivariate analysis (including physical activity, work patterns and sitting time) confirmed that full-time and part-time working women (but not 'home duties' women) were less likely to report BMI > or =25 kg/m(2) than full-time working men (full-time: OR=0.44, CI: 0.25-0.78; part-time: OR=0.45, CI: 0.24-0.86), but the OR for BMI > or =25 among those in the high sitting category was attenuated (OR=1.61, CI 0.96-2.71). CONCLUSIONS: The findings suggest a need for inclusion of measures of both activity and inactivity in future studies, so that the complex relationships between these behavioural determinants of BMI can be clarified.

Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomized study.

BACKGROUND: There are no currently approved methods for the screening and early detection of lung cancer. We compared the ability of conventional white-light bronchoscopy (WLB) and laser-induced fluorescence endoscopy (LIFE) to detect preneoplastic lung lesions in a randomized trial in which both the order of the procedures and the bronchoscopists were randomly assigned. METHODS: The study included high-risk subjects enrolled because of a cigarette smoking history of at least 30 pack-years, an air-flow obstruction, and either an abnormal sputum cytology (n = 48) or a previous or suspected lung cancer (n = 7). LIFE and WLB were performed on all patients. Biopsy specimens were assessed for histologic abnormalities, including the presence of angiogenic squamous dysplasia. All statistical tests were two-sided. RESULTS: A total of 391 biopsy specimens were taken from the 55 patients. Thirty-two patients (58%; 95% confidence interval [CI] = 44% to 71%) had at least one biopsy with moderate or severe dysplasia, and 19 (59%; 95% CI = 41% to 76%) of these patients could be diagnosed based solely on the results of LIFE. LIFE was statistically significantly more sensitive than WLB for detecting moderate dysplasia or worse (68.8% versus 21.9%, respectively) (difference = 46.9%; 95% CI = 25% to 68%; P< .001). The relative sensitivities (WLB = 1.0) were 3.1 (95% CI = 1.6 to 6.3) for LIFE and 3.7 (95% CI = 1.9 to 7.3) for LIFE and WLB combined. LIFE was less specific than WLB (69.6% versus 78.3%, respectively; P = .45), but the difference was not statistically significant. The relative specificities (WLB = 1.0) were 0.9 for LIFE (95% CI = 0.6 to 1.3) and 0.6 (95% CI = 0.4 to 1.0) for LIFE and WLB combined. The results were similar regardless of the order of the procedures or the order of the bronchoscopists. Also, LIFE was better at identifying angiogenic squamous dysplasia lesions than WLB (detection ratio [DR], which indicates the relative likelihood of getting a positive result in a sample with dysplasia compared with one without, for LIFE = 1.39 [95% CI = 1.17 to 1.65] versus DR for WLB = 0.67 [95% CI = 0.38 to 1.21]). CONCLUSION: LIFE was more sensitive than WLB in detecting preneoplastic bronchial changes in high-risk subjects. The prognostic implication of this finding is not yet clear.

Polymorphisms in pilin glycosylation Locus of Neisseria meningitidis expressing class II pili.

We have located a locus, pgl, in Neisseria meningitidis strain NMB required for the glycosylation of class II pili. Between five and eight open reading frames (ORFs) (pglF, pglB, pglC, pglB2, orf2, orf3, orf8, and avtA) were present in the pgl clusters of different meningococcal isolates. The Class I pilus-expressing strains Neisseria gonorrhoeae MS11 and N. meningitidis MC58 each contain a pgl cluster in which orf2 and orf3 have been deleted. Strain NMB and other meningococcal isolates which express class II type IV pili contained pgl clusters in which pglB had been replaced by pglB2 and an additional novel ORF, orf8, had been inserted between pglB2 and pglC. Insertional inactivation of the eight ORFs of the pgl cluster of strain NMB showed that pglF, pglB2, pglC, and pglD, but not orf2, orf3, orf8, and avtA, were necessary for pilin glycosylation. Pilin glycosylation was not essential for resistance to normal human serum, as pglF and pglD mutants retained wild-type levels of serum resistance. Although pglB2 and pglC mutants were significantly sensitive to normal human serum under the experimental conditions used, subsequent examination of the encapsulation phenotypes revealed that pglB2 and pglC mutants expressed almost 50% less capsule than wild-type NMB. A mutation in orf3, which did not affect pilin glycosylation, also resulted in a 10% reduction in capsule expression and a moderately serum sensitive phenotype. On the basis of these results we suggest that pilin glycosylation may proceed via a lipid-linked oligosaccharide intermediate and that blockages in this pathway may interfere with capsular transport or assembly.

Transcriptional regulation of divergent capsule biosynthesis and transport operon promoters in serogroup B Neisseria meningitidis.

The clinically important serogroups B, C, Y, and W-135 of Neisseria meningitidis produce sialic acid capsules that are critical in pathogenesis. In each of these serogroups, the capsule transport (ctrABCD) and capsule biosynthesis (synABCD) operons are divergently transcribed from putative promoters located in a 134-bp intergenic region (J. S. Swartley, J. H. Ahn, L. J. Liu, C. M. Kahler, and D. S. Stephens, J. Bacteriol. 178:4052-4059, 1996). In this study we further assessed the role of the intergenic sequence in the transcriptional regulation of the sialic acid capsules of N. meningitidis. Insertional mutagenesis or deletions of the 134-bp sequence in the serogroup B meningococcal strain NMB resulted in a marked reduction or elimination of ctrABCD and synABCD transcription, with a concomitant loss of encapsulation. Chromosomal transcriptional lacZ-ermC reporter fusions of syn and ctr promoters were constructed through allelic exchange. Using these constructs, both operons were found to be constitutively transcribed in meningococci, the biosynthesis operon about fourfold higher than the transport operon. Both promoters showed increased activity during stationary-phase growth. In addition to the promoters, a 70-bp 5' untranslated region (UTR) upstream of synA was found to have a direct repeat and an inverted repeat that overlapped three putative integration host factor binding sites. Mutation of this 70-bp UTR and of the direct repeat upregulated both syn and ctr transcription. Regulation through the synA UTR was absent in a K1 Escherichia coli strain that produces identical capsular polysaccharide, implicating species-specific regulation. Meningococcal sialic acid capsule expression is initiated by divergent promoters in a 134-bp intergenic region, is repressed at the transcriptional level by the 5' UTR of synA, is increased during stationary-phase growth, and shows species-specific regulation. Transcriptional regulation is another important control point for sialic capsule expression in N. meningitidis.

12/15-lipoxygenase translocation enhances site-specific actin polymerization in macrophages phagocytosing apoptotic cells.

The enzyme 12/15-lipoxygenase (12/15-LO) introduces peroxyl groups in a position-specific manner into unsaturated fatty acids in certain cells, but the role of such enzymatic lipid peroxidation remains poorly defined. Here we report a novel function for 12/15-LO in mouse peritoneal macrophages. When macrophages were coincubated with apoptotic cells, the enzyme translocated from cytosol to the plasma membrane and was more extensively concentrated at sites where macrophages bound apoptotic cells, colocalizing with polymerized actin of emerging filopodia. Disruption of F-actin did not prevent the 12/15-LO translocation. In contrast, inhibition of the 12/15-LO activity, or utilization of genetically engineered macrophages in which the 12/15-LO gene has been disrupted, greatly reduced actin polymerization in phagocytosing macrophages. Lysates of 12/15-LO-deficient macrophages had significantly lower ability to promote in vitro actin polymerization than the lysates of wild type macrophages. These studies suggest that the 12/15-LO enzyme plays a major role in local control of actin polymerization in macrophages in response to interaction with apoptotic cells.

exl, an exchangeable genetic island in Neisseria meningitidis.

The genetic structure and evolution of a novel exchangeable meningococcal genomic island was defined for the important human pathogen Neisseria meningitidis. In 125 meningococcal strains tested, one of three unrelated nucleotide sequences, designated exl (exchangeable locus), was found between a gene required for heme utilization, hemO, and col, encoding a putative Escherichia coli collagenase homologue. The 5' boundary of each exl cassette was the stop codon of hemO, whereas the 3' boundary was delineated by a 33-bp repeat containing neisserial uptake sequences located downstream of col. One of the three alternative exl cassettes contained the meningococcal hemoglobin receptor gene, hmbR (exl3). In other meningococcal strains, hmbR was absent from the genome and was replaced by either a nucleotide sequence containing a novel open reading frame, exl2, or a cassette containing exl3. The proteins encoded by exl2 and exl3 had no significant amino acid homology to HmbR but contained six motifs that are also present in the lipoprotein components of the lactoferrin (LbpB), transferrin (TbpB), and hemoglobin-haptoglobin (HpuA) uptake systems. To determine the evolutionary relationships among meningococci carrying hmbR, exl2, or exl3, isolates representing 92 electrophoretic types were examined. hmbR was found throughout the population structure of N. meningitidis (genetic distance, >0.425), whereas exl2 and exl3 were found in clonal groups at genetic distances of <0.2. The commensal neisserial species were identified as reservoirs for all of the exl cassettes found in meningococci. The structure of these cassettes and their correlation with clonal groups emphasize the extensive gene pool and frequent horizontal DNA transfer events that contribute to the evolution and virulence of N. meningitidis.

Too wet to exercise? Leaking urine as a barrier to physical activity in women.

Leaking urine is frequently mentioned (anecdotally) by women as a barrier to physical activity. The aim of this paper was to use results from the Australian Longitudinal Study on Women's Health (ALSWH) to explore the prevalence of leaking urine in Australian women, and to ascertain whether leaking urine might be a barrier to participation for women. More than 41,000 women participated in the baseline surveys of the ALSWH in 1996. More than one third of the mid-age (45-50 years) and older (70-75) women and 13% of the young women (18-23) reported leaking urine. There was a cross-sectional association between leaking urine and physical activity, such that women with more frequent urinary leakage were also more likely to report low levels of physical activity. More than one thousand of those who reported leaking urine at baseline participated in a follow-up study in 1999. Of these, more than 40% of the mid-age women (who were aged 48-53 in 1999), and one in seven of the younger (21-26 years) and older (73-79 years) women reported leaking urine during sport or exercise. More than one third of the mid-age women and more than one quarter of the older women, but only 7% of the younger women said they avoided sporting activities because of leaking urine. The data are highly suggestive that leaking urine may be a barrier to physical activity, especially among mid-age women. As current estimates suggest that fewer than half of all Australian women are adequately active for health benefit, health professionals could be more proactive in raising this issue with women and offering help through non-invasive strategies such as pelvic floor muscle exercises.

The emergence of Streptococcus pneumoniae resistant to macrolide antimicrobial agents: a 6-year population-based assessment.

From 1994 through 1999, the available isolates (4148 isolates) from active population-based surveillance of invasive pneumococcal disease in metropolitan Atlanta were serotyped and were tested for antimicrobial susceptibility. Macrolide-resistant isolates were studied for the presence of ermAM (a ribosomal methylase gene), mefE (a macrolide efflux gene), and tetM (the class M tetracycline resistance gene). Macrolide resistance increased from 16% of all invasive isolates in 1994 to 32% in 1999. Of the macrolide-resistant pneumococcal isolates studied, 99% contained genomic copies of mefE or ermAM. Isolates with ermAM were mainly serotypes 6B, 23F, 14, or 19F and contained tetM; mefE-associated isolates were predominantly serotypes 14, 6A, or 19F, and most did not contain tetM. The frequency of the ermAM-mediated phenotype in invasive Streptococcus pneumoniae remained stable over the 6-year surveillance. However, the mefE-mediated phenotype increased from 9% in 1994 to 26% of all isolates in 1999 and was noted in new serotypes. By 1999, 93% of the mefE-containing strains had minimum inhibitory concentrations >/=8 microgram/mL. Dissemination of the mefE determinant accounted for the rapid increase in the rate of macrolide resistance in our S. pneumoniae population.

Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer.

Lung carcinogenesis is assumed to be a multistep process, but detailed understanding of the sequential morphological and molecular changes preceding invasive lung cancer remains elusive. To better understand early lung carcinogenesis, we initiated a program of fluorescence bronchoscopy in smokers at high risk for lung cancer. In the bronchial biopsies from these subjects, we observed a unique lesion consisting of capillary blood vessels closely juxtaposed to and projecting into metaplastic or dysplastic squamous bronchial epithelium, angiogenic squamous dysplasia (ASD). Serial sections of the capillary projections confirmed that they represent intramucosal capillary loops. Microvessel density in ASD was elevated in comparison to normal mucosa (P = 0.0003) but not in comparison to other forms of hyperplasia or dysplasia. ASD thus represents a qualitatively distinct form of angiogenesis in which there is architectural rearrangement of the capillary microvasculature. Genetic analysis of surface epithelium in a random subset of lesions revealed loss of heterozygosity at chromosome 3p in 53% of ASD lesions. No confirmed p53 mutations were identified. Compared with normal epithelium, proliferative activity was markedly elevated in ASD lesions. ASD occurred in 54 of 158 (34%) high-risk smokers without carcinoma and in 6 of 10 patients with squamous carcinoma who underwent fluorescence bronchoscopy. One early-stage invasive carcinoma was noteworthy for the occurrence of ASD juxtaposed to invasive tumor. Seventy-seven (59%) of the ASD lesions were detected by abnormal fluorescence alone. Twenty bronchial sites (11 patients) were rebiopsied 1 year after the initial diagnosis. At nine (45%) of these sites, the lesion was found to persist. The lesion was not present in biopsies from 16 normal nonsmoker control subjects. The presence of this lesion in high-risk smokers suggests that aberrant patterns of microvascularization may occur at an early stage of bronchial carcinogenesis.