Panel 7 - Pathogenesis of otitis media - a review of the literature between 2015 and 2019.

OBJECTIVE: To perform a comprehensive review of the literature from July 2015 to June 2019 on the pathogenesis of otitis media. Bacteria, viruses and the role of the microbiome as well as the host response are discussed. Directions for future research are also suggested. DATA SOURCES: PubMed database of the National Library of Medicine. REVIEW METHODS: PubMed was searched for any papers pertaining to OM pathogenesis between July 2015 and June 2019. If in English, abstracts were assessed individually for their relevance and included in the report. Members of the panel drafted the report based on these searches and on new data presented at the 20th International Symposium on Recent Advances in Otitis Media. CONCLUSIONS: The main themes that arose in OM pathogenesis were around the need for symptomatic viral infections to develop disease. Different populations potentially having different mechanisms of pathogenesis. Novel bacterial otopathogens are emerging and need to be monitored. Animal models need to continue to be developed and used to understand disease pathogenesis. IMPLICATIONS FOR PRACTICE: The findings in the pathogenesis panel have several implications for both research and clinical practice. The most urgent areas appear to be to continue monitoring the emergence of novel otopathogens, and the need to develop prevention and preventative therapies that do not rely on antibiotics and protect against the development of the initial OM episode.

Soluble epoxide hydrolase activity and pharmacologic inhibition in horses with chronic severe laminitis.

BACKGROUND: The roles of soluble epoxide hydrolase and lipid mediators in inflammatory and neuropathic pain could be relevant in laminitis pain management. OBJECTIVES: To determine soluble epoxide hydrolase (sEH) activity in the digital laminae, sEH inhibitor potency in vitro, and efficacy of a sEH inhibitor as an adjunct analgesic therapy in chronic laminitic horses. STUDY DESIGN: In vitro experiments and clinical case series. METHODS: sEH activity was measured in digital laminae from euthanised healthy and laminitic horses (n = 5-6/group). Potency of 7 synthetic sEH inhibitors was determined in vitro using equine liver cytosol. One of them (t-TUCB; 0.1 mg/kg bwt i.v. every 24 h) was selected based on potency and stability, and used as adjunct therapy in 10 horses with severe chronic laminitis (Obel grades 2, one horse; 3-4, nine horses). Daily assessments of forelimb lifts, pain scores, physiologic and laboratory examinations were performed before (baseline) and during t-TUCB treatment. Data are presented as mean ± s.d. and 95% confidence intervals (CI). RESULTS: sEH activity in the digital laminae from laminitic horses (0.9±0.6 nmol/min/mg; 95% CI 0.16-1.55 nmol/min/mg) was significantly greater (P = 0.01) than in healthy horses (0.17±0.09 nmol/min/mg; CI 0.07-0.26 nmol/min/mg). t-TUCB as an adjunct analgesic up to 10 days (4.3±3 days) in laminitic horses was associated with significant reduction in forelimb lifts (36±22%; 95% CI 9-64%) and in pain scores (18±23%; 95% CI 2-35%) compared with baseline (P = 0.04). One horse developed gas colic and another corneal vascularisation in a blind eye during treatment. No other significant changes were observed. MAIN LIMITATIONS: Absence of control group and evaluator blinding in case series. CONCLUSIONS: sEH activity is significantly higher in the digital laminae of actively laminitic compared with healthy horses, and use of a potent inhibitor of equine sEH as adjunct analgesic therapy appears to decrease signs of pathologic pain in laminitic horses.

Plasma concentrations, analgesic and physiological assessments in horses with chronic laminitis treated with two doses of oral tramadol.

REASONS FOR PERFORMING STUDY: Laminitis is a painful disease for which adequate pain management remains a challenging and largely unmet medical need. OBJECTIVES: To investigate plasma concentrations, analgesic and physiological effects of 2 doses of tramadol in horses with chronic laminitis. STUDY DESIGN: Nonrandomised trial. METHODS: Four horses with naturally occurring chronic laminitis received 5 mg/kg bwt and then 10 mg/kg bwt tramadol orally every 12 h for one week with a one-week washout between. Noninvasive arterial blood pressure, heart and respiratory rates, intestinal sounds and forelimb off-loading frequency were evaluated before and during treatments. Plasma tramadol and metabolite (M1 and M2) concentrations were measured on predetermined days and times after the morning dosing. RESULTS: Forelimb off-loading frequency decreased significantly with 10 mg/kg bwt (40%, P = 0.02) but not with 5 mg/kg bwt (9%, P = 0.4). Physiological variables did not change significantly with either treatment. For 5 and 10 mg/kg bwt treatments, respectively, individual maximum plasma concentrations (µg/l) ranged from 329 to 728 and 628 to 1330 (tramadol), 12-24 and 32-80 (M1), and 90-157 and 239-362 (M2). Respective median area under the concentration vs. time curves (h µg/l) were 727 and 1426, 33 and 88, 303 and 1003. CONCLUSIONS: Twice daily oral tramadol at 10 mg/kg bwt may produce analgesic plasma levels in horses with chronic laminitis.

Retinal ganglion cell and inner plexiform layer thickness measurements in regions of severe visual field sensitivity loss in patients with glaucoma.

PURPOSE: To better understand the effects of severe glaucoma on the thickness of the retinal ganglion cell (RGC) and inner plexiform (IP) layers measured with frequency-domain optical coherence tomography. METHODS: In experiment 1, macular cube scans were obtained in 11 patients with glaucoma and the thickness of both the RGC and IP layers were measured at locations corresponding to 3, 5, and 7° eccentricity. For patients, only locations with total deviation losses of -15 dB or worse on perimetry were included. In experiment 2, higher resolution, horizontal midline scans were obtained from 30 controls in order to obtain a precise measure of the thickness of the RGC and IP layers of the healthy retina. RESULTS: In regions of severe field loss (experiment 1), glaucoma decreased the thickness of both layers, leaving a residual layer. The residual thickness of the IP layer was larger than the residual thickness of the RGC layer. In healthy controls (experiment 2), the RGC layer was about 57% of the RGC+IP layer thickness at 3° as compared with only 36% at 10°, in agreement with a recent histological study. CONCLUSION: Glaucomatous optic neuropathy, with severe losses in visual field sensitivity, decreases the thickness of both the RGC and IP layers, but leaves a residual thickness of both. The IP layer contributes slightly more than the RGC to this residual, even just outside the center of the fovea where the RGC layer thickness exceeds the IP layer thickness in controls.

In utero exposure to benzo(a)pyrene predisposes offspring to cardiovascular dysfunction in later-life.

In utero exposure of the fetus to benzo(a)pyrene [B(a)P], a polycyclic aromatic hydrocarbon, is thought to dysregulate cardiovascular development. To investigate the effects of in utero B(a)P exposure on cardiovascular development, timed-pregnant Long Evans Hooded (LEH) rats were exposed to diluent or B(a)P (150, 300, 600 and 1200 µg/kg/BW) by oral gavage on embryonic (E) days E14 (the metamorphosing embryo stage) through E17 (the 1st fetal stage). There were no significant effects of in utero exposure to B(a)P on the number of pups born per litter or in pre-weaning growth curves. Pre-weaning profiles for B(a)P metabolite generation from cardiovascular tissue were shown to be dose-dependent and elimination of these metabolites was shown to be time-dependent in exposed offspring. Systolic blood pressure on postnatal day P53 in the middle and high exposure groups of offspring were significantly elevated as compared to controls. Microarray and quantitative real-time PCR results were directly relevant to a biological process pathway in animal models for "regulation of blood pressure". Microarray and quantitative real-time PCR analysis revealed upregulation of mRNA expression for angiotensin (AngII), angiotensinogen (AGT) and endothelial nitric oxide synthase (eNOS) in exposed offspring. Biological network analysis and gene set enrichment analysis subsequently identified potential signaling mechanisms and molecular pathways that might explain the elevated systolic blood pressures observed in B(a)P-exposed offspring. Our findings suggest that in utero exposure to B(a)P predispose offspring to functional deficits in cardiovascular development that may contribute to cardiovascular dysfunction in later life.

Lex2B, a phase-variable glycosyltransferase, adds either a glucose or a galactose to Haemophilus influenzae lipopolysaccharide.

Nontypeable Haemophilus influenzae is a commensal that frequently causes otitis media and respiratory tract infections. The lex2 locus encodes a glycosyltransferase that is phase variably expressed and contributes to the significant intrastrain heterogeneity of lipopolysaccharide (LPS) composition in H. influenzae. In serotype b strains, Lex2B adds the second beta-glucose in the oligosaccharide extension from the proximal heptose of the triheptose inner core backbone; this extension includes a digalactoside that plays a role in resistance of the bacteria to the killing effect of serum. As part of our studies of the structure and genetics of LPS in nontypeable H. influenzae, we show here that there are allelic polymorphisms in the lex2B sequence that correlate with addition of either a glucose or a galactose to the same position in the LPS molecule across strains. Through exchange of lex2 alleles between strains we show that alteration of a single amino acid at position 157 in Lex2B appears to be sufficient to direct the alternative glucosyl- or galactosyltransferase activities. Allelic exchange strains express LPS with altered structure and biological properties compared to the wild-type LPS. Thus, Lex2B contributes to both inter- and intrastrain LPS heterogeneity through its polymorphic sequences and phase-variable expression.

Simple sequence repeats in Haemophilus influenzae.

Simple sequence repeat (SSRs) of DNA are subject to high rates of mutation and are important mediators of adaptation in Haemophilus influenzae. Previous studies of the Rd KW20 genome identified the primacy of tetranucleotide SSRs in mediating phase variation (the rapid reversible switching of gene expression) of surface exposed structures such as lipopolysaccharide. The recent sequencing of the genomes of multiple strains of H. influenzae allowed the comparison of the SSRs (repeat units of one to nine nucleotides in length) in detail across four complete H. influenzae genomes and then comparison with a further 12 genomes when they became available. The SSR loci were broadly classified into three groups: (1) those that did not vary; (2) those for which some variation between strains was observed but this could not be linked to variation of gene expression; and (3) those that both varied and were located in regions consistent with mediating phase variable gene expression. Comparative analysis of 988 SSR associated loci confirmed that tetranucleotide repeats were the major mediators of phase variation and extended the repertoire of known tetranucleotide SSR loci by identifying ten previously uncharacterised tetranucleotide SSR loci with the potential to mediate phase variation which were unequally distributed across the H. influenzae pan-genome. Further, analysis of non-tetranucleotide SSR in the 16 strains revealed a number of mononucleotide, dinucleotide, pentanucleotide, heptanucleotide, and octanucleotide SSRs which were consistent with these tracts mediating phase variation. This study substantiates previous findings as to the important role that tetranucleotide SSRs play in H. influenzae biology. Two Brazilian isolates showed the most variation in their complement of SSRs suggesting the possibility of geographic and phenotypic influences on SSR distribution.

Eccentricity-dependent changes in local onset and offset responses in patients with progressive cone dystrophy.

Shinoda and colleagues hypothesized that patients with cone dystrophy (CD) might suffer from a selective ON-system deficit, based on the local nature of the disease [Shinoda, K, Ohde, H, Inoue, R, Ishida, S, Mashima, Y, & Oguchi, Y (2002). ON-pathway disturbance in two siblings. Acta Ophthalmologica Scandinavica, 80, 219-223]. The purpose of the current study was to test this hypothesis by examining onset and offset responses as a function of eccentricity in a group of patients with CD using long-duration LED stimuli. Nine patients with CD participated in this study (mean age of 36.1 years and visual acuity 20/200). For this study, the following measures were obtained: Humphrey threshold visual fields, standard multifocal ERGs (mfERGs) as well as mfERGs to long duration stimuli recorded using the Retiscan stimulator (Roland Instruments). This display contained 61 scaled hexagons and the LEDs were on for 100ms (180cd/m(2)) and off for 100ms. In addition, standard full-field photopic and flicker ERGs using Ganzfeld stimulation were obtained. For the control subjects, the onset responses were larger than the offset responses at all eccentricities; whereas for the patients, there was overlap between the amplitudes of the onset and offset responses. For the patients, the amplitude ratios (relative to the control data) indicated that the difference between the onset and offset responses was greatest for the central-most ring and this difference decreased with increasing eccentricity. For the onset responses, Humphrey thresholds and mfERG amplitudes, performance was poorest for the center ring and best for the most peripheral ring; for the offset responses, the opposite pattern of results was obtained. The differences in the pattern of results in the long duration mfERG data are consistent with a selective loss of the onset responses in our patient population.

Retinal nerve fibre thickness measured with optical coherence tomography accurately detects confirmed glaucomatous damage.

AIM: To assess the accuracy of optical coherence tomography (OCT) in detecting damage to a hemifield, patients with hemifield defects confirmed on both static automated perimetry (SAP) and multifocal visual evoked potentials (mfVEP) were studied. METHODS: Eyes of 40 patients with concomitant SAP and mfVEP glaucomatous loss and 25 controls underwent OCT retinal nerve fibre layer (RNFL), mfVEP and 24-2 SAP tests. For the mfVEP and 24-2 SAP, a hemifield was defined as abnormal based upon cluster criteria. On OCT, a hemifield was considered abnormal if one of the five clock hour sectors (3 and 9 o'clock excluded) was at <1% (red) or two were at <5% (yellow). RESULTS: Seventy seven (43%) of the hemifields were abnormal on both mfVEP and SAP tests. The OCT was abnormal for 73 (95%) of these. Only 1 (1%) of the 100 hemifields of the controls was abnormal on OCT. Sensitivity/specificity (one eye per person) was 95/98%. CONCLUSIONS: The OCT RNFL test accurately detects abnormal hemifields confirmed on both subjective and objective functional tests. Identifying abnormal hemifields with a criterion of 1 red (1%) or 2 yellow (5%) clock hours may prove useful in clinical practice.

Structural and functional assessment of the macular region in patients with glaucoma.

PURPOSE: To investigate the correlation of a structural measure of the macular area (optical coherence tomography (OCT)) with two functional measures (10-2 Humphrey visual field (HVF) and multifocal visual evoked potential (mfVEP)) of macular function. METHODS: 55 eyes with open-angle glaucoma were enrolled. The 10-2 HVF was defined as abnormal if clusters of > or =3 points with p<5%, one of which had p<1%, were present. The mfVEP was abnormal if probability plots had > or =2 adjacent points with p<1%, or > or =3 adjacent points with p<5% and at least one of these points with p<1%. Two criteria were used for the macular OCT: (I) > or =2 sectors with p<5% or 1 sector with p<1% and (II) 1 sector with p<5%. RESULTS: 54 of the 55 eyes showed an abnormal 10-2 HVF and 50 had central mfVEP defects. The two OCT criteria resulted in sensitivities of 85% and 91%. When both functional tests showed a defect (in 49 eyes), the OCT was abnormal in 45. For the OCT the outer and inner inferior regions were the most likely to be abnormal, and both functional techniques were most abnormal in the superior hemifield. CONCLUSIONS: Good agreement exists between macular thickness and functional defects in patients with glaucoma. Study of the macular region may provide a quantitative measure for disease staging and monitoring.

Elevated procalcitonin as a diagnostic marker in meningococcal disease.

Patients with meningococcal disease who seek medical attention can create a diagnostic dilemma for clinicians due to the nonspecific nature of the disease's presentation. This study assesses the diagnostic accuracy of procalcitonin levels in the setting of meningococcal disease. Two emergency department cohorts (A and B) were studied between 2002 and 2005, during the current epidemic of serogroup B meningococcal disease in New Zealand. Cohort A consisted of 171 patients, all with confirmed meningococcal disease (84 children, 87 adults). Cohort B consisted of a large (n=1,524) consecutively recruited population of febrile patients who presented to the emergency department, 28 of whom had confirmed meningococcal disease. Within the meningococcal disease cohort (cohort A), the geometric mean procalcitonin level was 9.9 ng/ml, with levels being higher in children than in adults (21.6 vs. 4.6 ng/ml, p=0.01). The overall sensitivity of elevated procalcitonin, using a cutoff of 2.0 ng/ml in children and 0.5 ng/ml in adults, was 0.93 (95%CI: 0.88-0.96). Despite the higher cutoff level for paediatric patients, a trend towards greater sensitivity existed in children (0.96 vs. 0.90; p=0.08). Elevated procalcitonin was correlated with whole blood meningococcal load (r=0.50) and Glasgow Meningococcal Sepsis Prognostic Score (r=0.40). Within the cohort of patients who were febrile on presentation (cohort B), the specificity of elevated procalcitonin in meningococcal disease was 0.85 (95% CI: 0.83-0.87), the positive and negative likelihood ratios were 6.1 and 0.08, respectively, and the sensitivity of elevated procalcitonin (0.93; 95% CI: 0.76-0.99) was corroborated. Measurement of procalcitonin is a useful tool in patients with nonspecific febrile illnesses when the possibility of meningococcal disease is present. The diagnostic accuracy surpasses that of current early laboratory markers, allowing results to be used to guide decisions about patient management.

The effects of glaucoma on the latency of the multifocal visual evoked potential.

AIMS: To determine the effect of glaucomatous damage on the latency of the multifocal visual evoked potential (mfVEP). METHODS: Monocular mfVEPs were recorded from a glaucoma group (n = 50) defined by a glaucomatous disc and an abnormal visual field and a control group (n = 47). 25 patients were characterised as normal tension glaucoma (NTG) and 25 as high tension glaucoma (HTG). Monocular and interocular latency analyses of the more affected eye were obtained using custom software. RESULTS: On interocular analysis, both the HTG and NTG groups showed a statistically significant increase in mean mfVEP latency with average relative latencies and percentage of points with significant delays of 1.7 ms and 10.3% (HTG) and 1.3 ms and 8.2% (NTG) compared to -0.3 ms and 2.7% (controls). On monocular analysis, only the HTG group showed a significant increase in latency with measures of 5.7 ms and 14.6% (HTG) compared to 3.2 ms and 10.6% (NTG) and 2.1 ms and 9.6% (controls). Using the 95th percentile of a normative group as the cut off, the sensitivity ranged from 20% to 38% and the specificity from 87% to 100% with the interocular analysis providing the best discrimination, CONCLUSION: Although up to 40% of patients showed delays in the mfVEP latency, these delays were modest, on average a few milliseconds. These results differ markedly from those of a recent conventional VEP study, which reported 100% sensitivity, 100% specificity, and an average delay that exceeded 25 ms.

Changes in the threshold of fetal lung maturity testing and neonatal outcome of infants delivered electively before 39 weeks gestation: implications and cost-effectiveness.

OBJECTIVE: To compare the neonatal outcome of infants delivered before 39 weeks' gestation following documentation of fetal lung maturity before and after the lamellar body count (LBC) threshold was increased from 30,000 to 50,000 LB/ul. We discuss the algorithm employed for testing fetal lung maturity, the cost of testing and potential savings. MATERIAL AND METHODS: We studied the outcome of infants delivered electively before 39 weeks' gestation after fetal lung maturity was documented by amniotic fluid analysis. We compared the outcome of neonates born before and after the LBC threshold was increased. RESULTS: Our cohort included 527 neonates who were divided into two groups: 264 who underwent fetal lung maturity studies before the change in LBC threshold and 263 who underwent testing after the change. In the first group, 158 neonates met the criteria of LBC >30,000 LB/ul and were delivered without further testing. The second group included 154 neonates who were mature by LBC >50,000 LB/ul and were delivered. Seven of the neonates born in the first group required admission to the neonatal intensive care unit (NICU), whereas in the second group only two neonates required admission (P = 0.02). Additionally, 16 neonates in the first group required respiratory assistance compared with six in the second group (P = 0.04). The overall neonatal complication rate was significantly higher in the first group (P = 0.001). CONCLUSION: Changing the LBC threshold resulted in a significant decrease in neonatal morbidity. Employing the algorithm, we described for testing fetal lung maturity is cost effective, and more importantly, represents sound evidence-based medical management.

Making electronic mail accessible: perspectives of people with acquired cognitive impairments, caregivers and professionals.

The primary objective of this study was to better understand the technology needs, barriers and strategies of individuals with acquired cognitive impairments (ACI) in order to design and modify technologies with potential for alleviating the diminished independence and social isolation common in this population. The authors hypothesized that (1) higher rates of computer use would be reported by younger, more highly educated individuals with ACI, those with less severe injuries and those with previous computer experience; (2) A low percentage of survey respondents would own their own computers; and (3) People with ACI would experience social isolation and report low frequency of connecting with important people who live far away. A total of 133 individuals with ACI, professionals and care providers completed the survey. To gain more specific information, seven focus groups were conducted with 66 individuals with ACI and 20 care providers. Finally, 10 current email users participated in structured conversations, detailing their strategies for using email. The survey revealed that 80% of subjects with ACI reported owning a computer. Age and education were not predictors of computer use, but individuals whose ACI was the result of more severe injuries were less likely to use computers. As expected, respondents reported that maintaining contact with distant loved ones is problematic. The focus groups and conversations provided more detail about the communication needs of the population and the relative advantages and disadvantages of email compared with telephone and mail. Participants also identified barriers to email use they had encountered or feared they would encounter when using email. A number of accommodations to overcome these barriers were suggested. The results of the survey, focus groups and conversations confirmed the utility of email and other technologies for people with ACI and the need to make these technologies more accessible. The results and suggestions provided by the focus groups and interviews are being used in the design of Think and Link, an email interface for use by individuals with ACI.

Multifocal visual evoked potentials to cone specific stimuli in patients with retinitis pigmentosa.

Our aim was to determine whether patients with retinitis pigmentosa show differences in L- and M-cone multifocal visual evoked potential (mfVEP) responses that are eccentricity dependent, as has been shown for control subjects. Second, we compared the losses for mfVEPs to losses on achromatic visual field and multifocal electroretinogram (mfERG) measures in the patients. Monocular mfVEPs were recorded to a pattern reversing display that modulated only the L- or M-cones. Also, standard automated achromatic visual fields and mfERGs were obtained. For the control subjects, the ratio of L-cone to M-cone mfVEP amplitudes increased as a function of retinal eccentricity. For the patients, the ratio did not vary with eccentricity. For all measures, responses were least affected for the first ring (central 2.4 degrees ) and most affected for the third ring (11.6 degrees - 44.4 degrees ). For the first ring, mfERG amplitudes were more impaired than were the mfVEPs or the visual field thresholds. For most of the patients, there was local response correspondence among our measures of visual function.

Interpreting the multifocal visual evoked potential: the effects of refractive errors, cataracts, and fixation errors.

AIM: To understand how refractive errors, cataracts, and fixation errors affect multifocal visual evoked potential (mfVEP) responses. METHODS: Monocular mfVEP responses were obtained using a pattern reversal dartboard display. For the control condition, visual acuity was corrected to > or =20/20 and foveal fixation was maintained. The right eye was tested under the following conditions: simulated refractive error, simulated cataract, steady eccentric fixation, and unsteady fixation. RESULTS: No subject demonstrated significant abnormalities under control conditions. For the simulated refractive error condition, significant centrally located abnormalities were seen for all subjects. For the simulated cataract condition, significant abnormalities were found for three subjects. The steady eccentric fixation condition yielded abnormalities in both eyes for all subjects while the unsteady fixation condition yielded significant central abnormalities in the tested eye. With eccentric and unsteady fixation conditions, all subjects had at least one sector with a waveform polarity reversal. CONCLUSIONS: While the mfVEP is a useful tool for identifying local optic nerve damage or ruling out non-organic aetiology of visual field defects, factors such as uncorrected refractive errors, cataract, eccentric fixation, and unsteady fixation can produce apparent field defects on the mfVEP. With care, these problems can be correctly identified.

Atypical multifocal ERG responses in patients with diseases affecting the photoreceptors.

The purpose of this study was to investigate atypical multifocal ERG (mfERG) responses for patients with diseases that can affect the photoreceptors. MfERGS were obtained from seven patients with retinitis pigmentosa (RP), three with progressive cone dystrophy (CD) and eight with diabetic retinopathy (DR). Both first- and second-order kernel responses were analyzed. The amplitudes and implicit times of the first-order responses were compared to those obtained from age-similar controls. For the first slice of the second-order response, the root-mean-square (RMS) and the signal-to-noise ratio (SNR) of each response were calculated. Achromatic visual fields were also obtained from each subject. For the three groups of patients, first-order responses with relatively large amplitudes, broad-shaped waveforms and markedly increased implicit times had non-measurable second-order responses. These responses were associated with areas of decreased visual field sensitivity. As RP, CD and DR affect the outer retina, the results are consistent with damage to the outer plexiform layer rather than damage to the inner retina.

The changing face of tuberculosis control in a rural district of New Zealand.

SETTING: Waikato Health District (WHD), New Zealand. OBJECTIVE: To describe the changing epidemiology of TB in the WHD and the factors responsible for this. DESIGN: Descriptive epidemiological study of all notified TB cases from the WHD from 1 January 1992 to 31 December 2001. Major outcome measures were delay of diagnosis and treatment outcome. RESULTS: There were 244 cases included. Over the 10-year period, TB incidence has remained stable in the WHD. There has been a significant reduction of TB in the Maori population (from 30.3 to 12.5/100,000, P = 0.03). This has been matched by a rise in the overseas-born population (from 4.6 to 21.2/100,000, P = 0.04). Tuberculosis became a predominantly urban disease during the study period. Delay in diagnosis (>4 weeks) occurred in 85% of cases, with significantly more delays in older age groups. Use of directly observed therapy (OR 3.65, 95%CI 1.24-10.76), and being a migrant (OR 3.52, 95%CI 1.74-7.09), were significantly associated with improved treatment outcome. CONCLUSION: A significant change in the epidemiology of TB has occurred over the last decade. Tuberculosis control strategies need to be developed to effectively diagnose and treat patients from diverse cultural backgrounds.

Inhaled benzo(a)pyrene impairs long-term potentiation in the F1 generation rat dentate gyrus.

The purpose of this study is to provide a point of reference regarding the neurotoxic effects resulting from exposure to environmental contaminants. Benzo(a)pyrene is a member of the polycyclic aromatic hydrocarbon (PAH) family and it is a by-product of combustion processes. Thus, persons living near factories or hazardous waste sites face the danger of exposure through contact with contaminated air, water and soil. In an effort to understand the impact of environmental contaminants, we have investigated the effects of gestational B(a)P aerosol exposure on long-term potentiation (LTP), a cellular correlate of learning and memory in the F1 generation. Briefly, timed-pregnant rats were exposed to B(a)P via nose-only inhalation on gestation days 11-21 for 4 hr per day. Dams were maintained to term and pups were weaned on postnatal day 30. Subsequent electrophysiological studies during postnatal days 60-70 revealed a diminution in LTP across the perforant path-granular cells synapses in the hippocampus of F1 generation animals that were transplacentally exposed to B(a)P aerosol relative to unexposed controls. Additionally, NMDA receptor subunit 1 (NR1) protein was found to be downregulated in the hippocampus of B(a)P exposed F1 generation animals. Taken together, our results suggest that gestational exposure to B(a)P aerosol attenuates the capacity for LTP in the F1 generation.