Short-chain fatty acids induce tissue plasminogen activator in airway epithelial cells via GPR41&43.

BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous chronic inflammatory disease generally divided based on the presence or absence of nasal polyps (NPs). One of the features of NPs is excessive fibrin deposition, which is associated with down-regulation of tissue plasminogen activator (t-PA) in NPs. As t-PA is expressed in epithelial cells, and epithelium is readily accessible to topical therapies, identifying compounds that can mediate the induction of t-PA would be a potential new strategy for the treatment of NPs. OBJECTIVE: The objective of this study was to determine whether short-chain fatty acids (SCFAs) can induce t-PA in airway epithelial cells via their known receptors GPR41 and GPR43. METHODS: We performed immunohistochemistry (IHC) to determine whether receptors for SCFAs, known as G protein-coupled receptor 41/free fatty acid receptor 3 (GPR41/FFAR3) and GPR43/FFAR2, are expressed in nasal tissue. Primary normal human bronchial epithelial (NHBE) cells were stimulated with different concentrations of SCFAs to test induction of t-PA, which was analysed by expression of mRNA and protein. Mediation of responses by SCFA receptors was evaluated by specific receptor gene silencing with siRNA. RESULTS: Immunohistochemistry study revealed that airway epithelial cells expressed GPR41 and GPR43. Acetic acid, propionic acid, butyric acid and valeric acid significantly induced t-PA expression from two- to tenfolds. The strongest inducer of t-PA from NHBE cells was propionic acid; cells stimulated with propionic acid released t-PA into the supernatant in its active form. Gene silencing of GPR41 and GPR43 revealed that induction of t-PA by SCFAs was dependent upon both GPR41 and GPR43. CONCLUSIONS AND CLINICAL RELEVANCE: Short-chain fatty acids were shown to induce airway epithelial cell expression of t-PA via GPR41 and GPR43. Topical delivery of potent compounds that activate these receptors may have value by reducing fibrin deposition and shrinking nasal polyp growth.

Chronic airway inflammation provides a unique environment for B cell activation and antibody production.

BACKGROUND: B cells play many roles in health and disease. However, little is known about the mechanisms that drive B cell responses in the airways, especially in humans. Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways that affects 10% of Europeans and Americans. A subset of CRS patients develop nasal polyps (NPs), which are characterized by type 2 inflammation, eosinophils and group 2 innate lymphoid cells (ILC2s). We have reported that NP contain elevated levels of B cells and antibodies, making NP an ideal system for studying B cells in the airways. OBJECTIVE: We sought to determine the mechanisms that drive B cell activation and antibody production during chronic airway inflammation. METHODS: We analysed B cells from NP or tonsil, or after ILC2 coculture, by flow cytometry. Antibody production from tissue was measured using Luminex assays and the frequency of antibody-secreting cells by ELISpot. Formation of B cell clusters was assessed using immunohistochemistry. Expression of genes associated with B cell activation and class switch recombination was measured by qRT-PCR. RESULTS: NP contained significantly elevated frequencies of plasmablasts, especially those that expressed the extrafollicular marker Epstein-Barr virus-induced protein 2 (EBI2), but significantly fewer germinal centre (GC) B cells compared with tonsil. Antibody production and the frequency of antibody-secreting cells were significantly elevated in NP, and there was evidence for local class switch recombination in NP. Finally, ILC2s directly induced EBI2 expression on B cells in vitro. CONCLUSIONS AND CLINICAL RELEVANCE: Our data suggest there is a unique B cell activation environment within NP that is distinct from classic GC-mediated mechanisms. We show for the first time that ILC2s directly induce EBI2 expression on B cells, indicating that ILC2s may play an important role in B cell responses. B cell-targeted therapies may provide new treatment options for CRSwNP.

Live birth sex ratios and father's geographic origins in Jerusalem, 1964-1976.

OBJECTIVE: To examine whether ancestry influenced sex ratios of offspring in a birth cohort before parental antenatal sex selection influenced offspring sex. METHODS: We measured the sex ratio as the percent of males according to countries of birth of paternal and maternal grandfathers in 91,459 live births from 1964 to 1976 in the Jerusalem Perinatal Study. Confidence limits (CI) were computed based on an expected sex ratio of 1.05, which is 51.4% male. RESULTS: Of all live births recorded, 51.4% were male. Relative to Jewish ancestry (51.4% males), significantly more males (1,761) were born to Muslim ancestry (54.5, 95% CI = 52.1-56.8, P = 0.01). Among the former, sex ratios were not significantly associated with paternal or maternal age, education, or offspring's birth order. Consistent with a preference for male offspring, the sex ratio decreased despite increasing numbers of births over the 13-year period. Sex ratios were not affected by maternal or paternal origins in North Africa or Europe. However, the offspring whose paternal grandfathers were born in Western Asia included fewer males than expected (50.7, 50.1-51.3, P = 0.02), whether the father was born abroad (50.7) or in Israel (50.8). This was observed for descendents of paternal grandfathers born in Lebanon (47.6), Turkey (49.9), Yemen & Aden (50.2), Iraq (50.5), Afghanistan (50.5), Syria (50.6), and Cyprus (50.7); but not for those from India (51.5) or Iran (51.9). The West Asian group showed the strongest decline in sex ratios with increasing paternal family size. CONCLUSIONS: A decreased sex ratio associated with ancestry in Western Asia is consistent with reduced ability to bear sons by a subset of Jewish men in the Jerusalem cohort. Lower sex ratios may be because of pregnancy stress, which may be higher in this subgroup. Alternatively, a degrading Y chromosome haplogroup or other genetic or epigenetic differences on male germ lines could affect birth ratios, such as differential exposure to an environmental agent, dietary differences, or stress. Differential stopping behaviors that favor additional pregnancies following the birth of a daughter might exacerbate these lower sex ratios.

Elevated presence of myeloid dendritic cells in nasal polyps of patients with chronic rhinosinusitis.

BACKGROUND: Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the mechanism underlying the onset and amplification of this inflammation has not been fully elucidated. Dendritic cells (DCs) are major antigen-presenting cells, central inducers of adaptive immunity and critical regulators of many inflammatory diseases. However, the presence of DCs in CRS, especially in nasal polyps (NPs), has not been extensively studied. OBJECTIVE: The objective of this study was to characterize DC subsets in CRS. METHODS: We used real-time PCR to assess the expression of mRNA for markers of myeloid DCs (mDCs; CD1c), plasmacytoid DCs (pDCs; CD303) and Langerhans cells (LCs; CD1a, CD207) in uncinate tissue (UT) from controls and patients with CRS as well as in NP. We assayed the presence of DCs by immunohistochemistry and flow cytometry. RESULTS: Compared to UT from control subjects (n = 15) and patients with CRS without NP (CRSsNP) (n = 16) and CRSwNP (n = 17), mRNAs for CD1a and CD1c were significantly elevated in NPs (n = 29). In contrast, CD207 mRNA was not elevated in NPs. Immunohistochemistry showed that CD1c(+) cells but not CD303(+) cells were significantly elevated in NPs compared to control subjects or patients with CRSsNP. Flow cytometric analysis showed that CD1a(+) cells in NPs might be a subset of mDC1s and that CD45(+) CD19(-) CD1c(+) CD11c(+) CD141(-) CD303(-) HLA-DR(+) mDC1s and CD45(+) CD19(-) CD11c(+) CD1c(-) CD141(high) HLA-DR(+) mDC2s were significantly elevated in NPs compared to UT from controls and CRSsNP, but CD45(+) CD11c(-) CD303(+) HLA-DR(+) pDCs were only elevated in NPs compared to control UT. CONCLUSION AND CLINICAL RELEVANCE: Myeloid DCs are elevated in CRSwNP, especially in NPs. Myeloid DCs thus may indirectly contribute to the inflammation observed in CRSwNP.

Reduced expression of antimicrobial PLUNC proteins in nasal polyp tissues of patients with chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is a disease characterized by inflammation of the nasal mucosa and paranasal sinuses. This inflammation may result in part from decreased epithelial barrier and innate immune responses, leading to frequent bacterial and fungal colonization. The objectives of this study were to investigate the expression of innate immune proteins of the palate lung and nasal epithelium clone (PLUNC) family in patients with CRS. METHODS: Nasal tissue samples were collected from control subjects and CRS patients with and without nasal polyps. Expression of the members of the PLUNC family was analyzed by real-time PCR. Expression of SPLUNC1 and LPLUNC2 proteins was analyzed by ELISA, immunoblot, and immunohistochemical analysis. RESULTS: Levels of mRNA for most of the members of the PLUNC family were profoundly reduced in nasal polyps (NPs) compared to uncinate tissue from control subjects or patients with CRS. LPLUNC2 and SPLUNC1 proteins were decreased in NPs of patients with CRS compared to uncinate tissue from control subjects. Immunohistochemical data revealed that within submucosal glands of sinonasal tissues, SPLUNC1 and LPLUNC2 were differentially expressed, in serous and mucous cells, respectively. The decrease in the expression of these molecules is probably explained by a decrease in the number of glands in NPs as revealed by correlations with levels of the glandular marker lactoferrin. CONCLUSIONS: Decreased SPLUNC1 and LPLUNC2 in NPs reflect a profound decrease in the number of submucosal glands. Decreased glands may lead to a localized defect in the production and release of glandular innate defense molecules.

Early eutrophication in the lower great lakes:.

New Evidence from Biogenic Silica in Sediments New evidence from studies of biogenic silica and diatoms in sediment cores indicates that eutrophication in the lower Great Lakes resulted from nutrient enrichment associated with early settlement and forest clearance. Diatom production peaked from 1820 to 1850 in Lake Ontario, at about 1880 in Lake Erie, but not until 1970 in Lake Michigan. This is the first reported sediment record of the silica-depletion sequence for the Great Lakes.

MEAD: an interdisciplinary study of the marine effects of atmospheric deposition in the Kattegat.

This paper summarises the results of the EU funded MEAD project, an interdisciplinary study of the effects of atmospheric nitrogen deposition on the Kattegat Sea between Denmark and Sweden. The study considers emissions of reactive nitrogen gases, their transport, transformations, deposition and effects on algal growth together with management options to reduce these effects. We conclude that atmospheric deposition is an important source of fixed nitrogen to the region particularly in summer, when nitrogen is the limiting nutrient for phytoplankton growth, and contributes to the overall eutrophication pressures in this region. However, we also conclude that it is unlikely that atmospheric deposition can, on its own, induce algal blooms in this region. A reduction of atmospheric nitrogen loads to this region will require strategies to reduce emissions of ammonia from local agriculture and Europe wide reductions in nitrous oxide emissions.

The reliability and validity of the Geriatric Depression Rating Scale administered by telephone.

OBJECTIVE: To evaluate prospectively the reliability and validity of the Geriatric Depression Scale administered by telephone (T-GDS) in patients undergoing outpatient comprehensive geriatric assessment. SUBJECTS: A total of 101 geriatric patients were evaluated in a 1-year period at the outpatient Geriatric Assessment Center of the University of Nebraska Medical Center. METHODS: The 30-item GDS was completed by all patients on three occasions: by telephone several days before their assessment, face-to-face during their assessment visit, and several days later, again by phone. During their assessment, all patients were evaluated by one of three geriatric psychiatrists who were blind to all GDS results. The test-retest reliability of the T-GDS was measured by comparing the results of the two phone interviews. The construct validity of the T-GDS was estimated by comparing the results of the initial T-GDS to the GDS obtained during the comprehensive assessment. The criterion validity of the T-GDS was estimated by comparing the results of the T-GDS with the clinical diagnosis of depression assigned by the psychiatrists. RESULTS: The individual items of the initial T-GDS showed substantial concordance with the second T-GDS (kappa range 0.35-0.75, mean = 0.52), and with the assessment GDS (kappa range 0.29-0.75, mean = 0.52). One item showed evidence of bias when comparing the two T-GDSs, and two items when comparing the initial T-GDS to the GDS done during the assessment. The mean number of symptomatic responses was not significantly different for the T-GDS versus assessment administration but did decline slightly when comparing the two T-GDSs. ROC curve analyses showed good agreement between the clinical diagnosis and the T-GDS. CONCLUSION: The GDS appears to maintain its reliability and validity when administered via telephone and thus may be useful for a variety of epidemiological and clinical purposes.

Running economy and distance running performance of highly trained athletes.

The purpose of the study was to determine the relationship between running economy and distance running performance in highly trained and experienced distance runners of comparable ability. Oxygen uptake (Vo2) during steady-state and maximal aerobic power (Vo2max) were measured during treadmill running using the open-circuit method. Distance running performance was determined in a nationally prominent 10 km race; all subjects (12 males) placed among the top 19 finishers. The subjects averaged 32.1 min on the 10 km run, 71.7 ml.kg-1.min-1 for Vo2max, and 44.7, 50.3, and 55.9 ml.kg-1.min-1 for steady-state Vo2 at three running paces (241, 268, and 295 m.min-1). The relationship between Vo2max and distance running performance was r = -0.12 (p = 0.35). The relationship between steady-state Vo2 at 241, 268 and 295 m.min-1 and 10 km time were r = 0.83, 0.82, and 0.79 (p < 0.01), respectively. Within this elite cluster of finishers, 65.4% of the variation observed in race performance time on the 10 km run could be explained by variation in running economy. It was concluded that among highly trained and experienced runners of comparable ability and similar Vo2max, running economy accounts for a large and significant amount of the variation observed in performance on a 10 km race.

Peak oxygen deficit during one- and two-legged cycling in men and women.

The objectives of this study were to determine the relationships of estimated active muscle mass and gender to anaerobic capacity, as measured by the peak oxygen deficit, and to compare these relationships with those for peak oxygen uptake (VO2peak). Fat-free leg volumes (FFLV), and one- and two-legged cycling peak oxygen deficit and VO2peak were determined in young, physically active men (N = 11) and women (N = 9). For men and women, mean (+/- SD) peak oxygen deficit for one-legged cycling (2.27 +/- 0.30 and 1.18 +/- 0.18 l) was 52% of that for two-legged cycling (4.40 +/- 0.62 and 2.25 +/- 0.28 l). For all subjects and both modes of exercise, there was a strong linear relation between peak oxygen deficit (1) and estimated active muscle mass (FFLV) (r = 0.94). This relation was the same in one- and two-legged cycling, but was different for men and women. For a given FFLV, the peak oxygen deficit was significantly higher (P < 0.05) in men than women by an average of 0.44 l. The relation of peak oxygen deficit to FFLV was significantly stronger than the relation of VO2peak to FFLV (r = 0.80). We conclude: (a) that the peak oxygen deficit is strongly related to the estimated active muscle mass during cycling; (b) that for a given estimated active muscle mass (FFLV), the peak oxygen deficit is higher in men than women; and (c) that the peak oxygen deficit is more strongly related than VO2peak to the estimated quantity of active muscle.

Peak oxygen deficit predicts sprint and middle-distance track performance.

The purpose of this study was to determine the value of the peak oxygen deficit (POD) as a predictor of sprint and middle-distance track performance. POD, peak blood lactate, VO2peak, lactate threshold, and running economy at 3.6 m.s-1 were measured during horizontal treadmill running in 22 male and 19 female competitive runners of different event specialties. Subjects also completed running performance trials at 100, 200, 400, 800, 1500, and 5000 m. Correlations of track performances with POD (ml.kg-1) (-0.66, -0.71, -0.71, -0.62, -0.52, and -0.40) were moderately strong at the sprint and middle distances, accounting for 44-50% of the performance variance at the three shortest distances. Correlations of track performances with peak blood lactate concentration were lower than with POD and accounted for approximately one-half as much of the performance variance (21-26%) at the three shortest distances. Multiple regression analyses indicated that the POD was the strongest metabolic predictor of 100-, 200- and 400-m performance, and that VO2peak was the strongest metabolic predictor of 800-, 1500-, and 5000-m performance. We conclude that the POD is a moderately strong predictor of sprint and middle-distance track performance.

Validation of the 12-min swim as a field test of peak aerobic power in young men.

The purposes of this study were to validate the 12-min swim as a field test of VO2max and to compare its validity with that of the 12-min run. Thirty-six young men completed 12-min swim, 12-min run, tethered swimming (TS) VO2peak, and treadmill running (TR) VO2peak tests within 3 wk. Mean (+/- SD) 12-min swim and run distances were 581 +/- 88 and 2797 +/- 290 m, and mean TS and TR VO2peak values were 50.3 +/- 6.2 and 57.2 +/- 5.5 ml.kg BW-1.min-1, respectively. Correlation coefficients and standard errors of estimate for predictions of TS VO2peak from the 12-min swim (0.40 and 5.7 ml.kg BW-1.min-1) and run (0.74 and 4.2 ml.kg BW-1.min-1) and for predictions of TR VO2peak from the 12-min swim (0.38 and 5.1 ml.kg BW-1.min-1) and run (0.88 and 2.6 ml.kg BW-1.min-1) indicated that the 12-min run was a more accurate predictor of TS or TR VO2peak than the 12-min swim. We conclude that the 12-min swim has relatively low validity as a field test of peak aerobic power and that it should not be considered an equally valid alternative to the 12-min run in young male recreational swimmers. However, the accuracy of predicting VO2peak from the 12-min swim is as good as some other commonly used methods, and, therefore, it may be adequate for fitness classification in situations in which a high level of accuracy is not needed.

Racemization of ketorolac in aqueous solution.

The racemization of ketorolac was studied in aqueous buffered solution at 25 and 80 degrees C and analyzed in detail with respect to the catalytic species in solution. The reaction has a U shaped pH rate profile at 80 degrees C with the pH of maximum stability occurring in the region of pH 3.0-7.5. A T90 value of 8 months was observed for a 1.5% (R)-ketorolac tromethamine solution at pH 7.4 and 25 degrees C. Additionally, the data shows that alternative salt forms are necessary in order to prepare a stable single isomer formulation. Alternative buffers, in particular phosphate buffer, provide formulations exhibiting a T90 greater than 2 years.

Phonation threshold pressure measurements during phonation by airflow interruption.

OBJECTIVE/HYPOTHESIS: Most methods to measure phonation threshold pressure (PTP) are clinically impractical because they are invasive. This report concerns an airflow interruption system developed to allow noninvasive estimation of (PTP) at different levels of vocal intensity. An estimation of PTP was made for normal subjects with normal larynges and no voice complaints and for individuals who had dysphonia associated with vocal polyps to compare the estimated minimal pressure across the glottis that was required to sustain phonation in the two conditions. STUDY DESIGN: This was a methodological study designed to measure an unanticipated PTP from a subject. METHODS: Subjects sustained a constant tone and the airflow was directed into a section of pipe with an airtight mask over the mouth and nose. The airflow, intramask pressure, and intensity of the acoustic output were recorded. A PTP was predicted from a difference between an estimate of the subglottal pressure and the vocal tract pressure at the point that phonation ceased after interruption of airflow. Eleven control subjects and 13 patients with vocal fold polyps were studied. In each population there were eight men and five women. The individuals in the group with vocal fold polyps averaged 39 years of age, and the control subject group averaged 49 years of age. Normal subjects produced a steady vowel /a/ at 75, 80, and 85 dB. Patients with polyps were unable to sustain phonation at these levels but were able to produce phonation at 65, 70, and 75 dB. The validity of the system was tested using a laryngeal model and in a patient with a normal larynx and voice who had a tracheotomy (placed for sleep apnea syndrome) which allowed direct measurement of subglottal pressure. RESULTS: The measured mean PTP levels (with standard deviation [SD]) for the control subjects were 2.38 (1.273), 2.67 (1.879), and 2.98 (2.23) cm H2O at 75, 80, and 85 dB, respectively. The measured mean PTP levels (with SD) for the patients with polyps were 4.79 (2.67), 5.85 (2.34), and 7.37 (3.26) cm H2O at 75, 80, and 85 dB, respectively. The differences in mean PTP between groups at 75, 80, and 85 dB were significant at P = .013, P = .017, and P = .010, respectively. CONCLUSIONS: The estimations of PTP for patients with vocal fold polyps were significantly higher than for the control subjects at three phonation levels.

Treatment of olfactory dysfunction, II: studies with minocycline.

OBJECTIVES/HYPOTHESIS: The treatment of anosmia has changed minimally since the early 1970s, despite dramatic advances in the understanding of the molecular biology of olfaction. Recent studies from the authors' laboratory have suggested that most common causes of clinical olfactory dysfunction, including rhinosinusitis, appear to be associated with increased apoptotic death of olfactory sensory neurons. This appears to result in a decline in the number of functioning mature olfactory sensory neurons, despite the capacity of the olfactory epithelium for regeneration. The current study evaluated the ability of the antibiotic minocycline to inhibit olfactory sensory neuron apoptosis. This drug is known to inhibit apoptosis separate from its anti-infective properties. Olfactory sensory neuron apoptosis was triggered by surgical deafferentation ("bulbectomy"), the standard experimental model. Earlier studies have indicated that bulbectomy and sinusitis invoke similar proteolytic enzyme cascades in olfactory sensory neurons. STUDY DESIGN: Histological analysis of animal olfactory tissue. METHODS: Mice underwent unilateral olfactory bulbectomy to induce apoptotic olfactory sensory neuron death, with and without 45 mg/kg intraperitoneal minocycline given 12 hours before surgery and every 12 hours until death. Mice were killed at 2 and 4 days after bulbectomy and assessed for activation of capsase-3 and olfactory sensory neuron survival by immunohistochemical analysis. RESULTS: Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals. CONCLUSION: Minocycline inhibits olfactory sensory neuron death in the face of a potent pro-apoptotic stimulus. This drug is well tolerated and is currently undergoing human trials for the management of a variety of neurological disorders associated with apoptosis. The current results suggest that minocycline may be efficacious in the management of peripheral olfactory loss as well.

Pathology of the olfactory mucosa: implications for the treatment of olfactory dysfunction.

OBJECTIVE: The pathology of the olfactory mucosa is poorly understood; however, most cases of hyposmia and anosmia appear to be associated with a decline in the number of functioning mature olfactory sensory neurons (OSNs). Under normal conditions, OSNs undergo apoptotic cell death at a baseline rate likely secondary to their exposed location in the nose. Regeneration of mature OSNs from precursors in the epithelium allows the animal to maintain an adequate number of neurons necessary for olfactory sensation. In many cases of olfactory dysfunction, this balance is apparently disturbed, with a net loss of OSNs. The current study will examine normal and diseased olfactory tissue for the presence of data demonstrating that the preferred mechanism of OSN cell death is apoptotic in both health and disease. The potential therapeutic implications will be discussed. STUDY DESIGN: Histologic analysis of human and animal olfactory tissue. METHODS: Normal and diseased human and animal olfactory mucosa were assessed for immunohistochemical evidence of apoptosis. RESULTS: Increased activity of the apoptotic effector enzyme caspase-3 was demonstrated in diseased olfactory mucosa in comparison with normal controls. CONCLUSION: These results indicate that a common pathway may mediate OSN cell death from a diverse set of pathologic insults including aging, trauma, and sinusitis. Interference with this pathway of cell death is currently the subject of intense pharmacotherapeutic research for the management of stroke and meningitis. These drugs may ultimately prove useful in the treatment of clinical olfactory dysfunction.

Apoptosis in the aging olfactory epithelium.

OBJECTIVES: Olfactory receptor neurons undergo apoptosis at a baseline rate, probably secondary to environmental damage even in the absence of gross disease. The study demonstrates age-related changes in expression of genes known to regulate apoptosis in the rat olfactory mucosa. These results are compared with gene expression in young rats and rats that have undergone surgical deafferentation of the olfactory receptor neurons. STUDY DESIGN: The olfactory mucosae from three groups of rats were studied: young, normal rats (age, 12 wk); old, normal rats (age, 24 mo); and young rats 9 days after bilateral removal of the olfactory bulb. Bulbectomy is known to produce an initial wave of apoptotic cell death in the population of olfactory neurons. At 9 days after the injury, the olfactory mucosae consist of an enhanced population of regenerating neurons destined to also undergo apoptosis, since their synaptic target (bulb) has been removed. METHODS: Ribonuclease protection assays and histological analysis of the three groups were performed. RESULTS: Ribonuclease protection assay analysis indicates that age induces increases in the expression of pro-apoptotic genes in the olfactory mucosae similar to the increase seen after deafferentation (bulbectomy). Specifically, the expression of procaspase-3 and bax was increased in aged animals and bulbectomized animals when compared with young, normal animals. CONCLUSIONS: Aging induces changes in gene expression in the olfactory mucosae that appear to favor apoptosis, probably associated with increased fragility of olfactory receptor neurons in older animals. These changes may, at least in part, explain the age-related decline in olfactory sensation and loss of olfactory receptor neurons seen in elderly patients.

Pathology of the olfactory epithelium: smoking and ethanol exposure.

OBJECTIVE: To investigate the effects of tobacco smoke on the olfactory epithelium. Cigarette smoking has been associated with hyposmia; however, the pathophysiology is poorly understood. The sense of smell is mediated by olfactory sensory neurons (OSNs) exposed to the nasal airway, rendering them vulnerable to environmental injury and death. As a consequence, a baseline level of apoptotic OSN death has been demonstrated even in the absence of obvious disease. Dead OSNs are replaced by the mitosis and maturation of progenitors to maintain sufficient numbers of neurons into adult life. Disruption of this balance has been suggested as a common cause for clinical smell loss. This current study will evaluate the effects of tobacco smoke on the olfactory mucosa, with emphasis on changes in the degree of OSN apoptosis. STUDY DESIGN: A rat model was used to assess the olfactory epithelium after exposure to tobacco smoke. METHODS: Rats were exposed to tobacco smoke alone (for 12 weeks), smoke plus dietary ethanol (for the final 5 weeks), or to neither (control). Immunohistochemical analysis of the olfactory epithelium was performed using an antibody to the active form of caspase-3. Positive staining for this form of the caspase-3 enzyme indicates a cell undergoing apoptotic proteolysis. RESULTS: Control rats demonstrated a low baseline level of caspase-3 activity in the olfactory epithelium. In contrast, tobacco smoke exposure triggered a dramatic increase in the degree of OSN apoptosis that affected all stages of the neuronal lineage. CONCLUSIONS: These results support the following hypothesis: smell loss in smokers is triggered by increased OSN death, which eventually overwhelms the regenerative capacity of the epithelium.

Birth weight and income: interactions across generations.

This paper attempts to answer a series of questions regarding the interaction of income and birth weight across generations. First, does the effect of the income of a mother during her pregnancy on her infant's birth weight depend on the family's birth weight history (genetic predisposition)? Second, does the effect of low birth weight status on adult life chances depend on income during early childhood? These questions have implications for the way we envision the biological and social worlds as interacting across generations. To address these issues, this study uses intergenerational data from the Panel Study of Income Dynamics, survey years 1968 through 1992. Results of sibling comparisons (family-fixed-effects models) demonstrate that maternal income has a significant impact on birth weight for those infants who are already at high risk hereditarily (i.e., who have a low birth weight parent). However, it is not clear whether income acts as a developmental buffer for low birth weight infants as their lives progress. These findings suggest the existence of biosocial interactions between hereditary predisposition and socio-economic environment.