Effect of photobiomodulation on vinblastine-poisoned murine HERS cells.

OBJECTIVE: The aim of this study was to investigate the effect of near-infrared (NIR) photobiomodulation on the proliferation and glutathione levels in murine Hertwig's epithelial root sheath (HERS) cells after poisoning with vinblastine. BACKGROUND: Photobiomodulation has been shown to improve wound healing in a number of animal models. There have been no studies on the effect of photobiomodulation on cancer-related chemotherapy injury to the cells that initiate tooth root growth. MATERIALS AND METHODS: Control groups consisted of murine HERS cells without vinblastine (VB-) and cells with vinblastine at 10, 20, and 30 ng/mL (VB10, VB20, and VB30). Experimental groups consisted of these same groups with light therapy (VB-L, VB10L, VB20L, and VB30L). The cells were exposed to vinblastine for 1 h. Photobiomodulation consisted of a 75-cm(2) gallium-aluminum-arsenide light-emitting diode (LED) array at an energy density of 12.8 J/cm(2), delivered with 50 mW/cm(2) power over 256 s. RESULTS: Vinblastine alone significantly decreased HERS cell proliferation and glutathione levels at all concentrations (VB10 [-55%, p < 1.0 × 10(-8)]; VB20 [-72%, p < 1.0 × 10(-9)]; VB30 [-80%, p < 1.0 × 10(-10)]; and VB10 [-36%, p < 0.0001]; VB20 [-49%, p < 1.0 × 10(-6)]; VB30 [-53%, p < 1.0 × 10(-7)] respectively). Photobiomodulation significantly increased cell proliferation at all levels of vinblastine exposure (VB10L [+50%, p < 0.0001]; VB20L [+45%, p < 0.05]; VB30 [+39%, p < 0.05]) but not of the control (+22%, p = 0.063). The photobiomodulation significantly increased glutathione production in all concentrations of vinblastine except 20 ng/mL (VB10L [+39%, p = 0.007]; VB20L [+19%, p = 0.087]; VB30 [+14%, p = 0.025]) and the control (+12%, p = 0.13). CONCLUSIONS: Photobiomodulation demonstrated an improvement in proliferation and glutathione levels in vinblastine-poisoned murine HERS cells.

Therapeutic photobiomodulation for methanol-induced retinal toxicity.

Methanol intoxication produces toxic injury to the retina and optic nerve, resulting in blindness. The toxic metabolite in methanol intoxication is formic acid, a mitochondrial toxin known to inhibit the essential mitochondrial enzyme, cytochrome oxidase. Photobiomodulation by red to near-IR radiation has been demonstrated to enhance mitochondrial activity and promote cell survival in vitro by stimulation of cytochrome oxidase activity. The present studies were undertaken to test the hypothesis that exposure to monochromatic red radiation from light-emitting diode (LED) arrays would protect the retina against the toxic actions of methanol-derived formic acid in a rodent model of methanol toxicity. Using the electroretinogram as a sensitive indicator of retinal function, we demonstrated that three brief (2 min, 24 s) 670-nm LED treatments (4 J/cm(2)), delivered at 5, 25, and 50 h of methanol intoxication, attenuated the retinotoxic effects of methanol-derived formate. Our studies document a significant recovery of rod- and cone-mediated function in LED-treated, methanol-intoxicated rats. We further show that LED treatment protected the retina from the histopathologic changes induced by methanol-derived formate. These findings provide a link between the actions of monochromatic red to near-IR light on mitochondrial oxidative metabolism in vitro and retinoprotection in vivo. They also suggest that photobiomodulation may enhance recovery from retinal injury and other ocular diseases in which mitochondrial dysfunction is postulated to play a role.

Renal failure and vestibular toxicity in an adolescent with cystic fibrosis receiving gentamicin and standard-dose ibuprofen.

Gentamicin and standard-dose ibuprofen were administered to an adolescent with cystic fibrosis who developed renal failure and severe vestibulotoxicity. A contributing factor was possible suboptimal intravascular volume status. Because of the potential severity of this drug interaction, hydration status and renal and vestibular functions should be closely monitored in patients receiving ibuprofen and intravenous aminoglycosides concomitantly.

Differential recovery of retinal function after mitochondrial inhibition by methanol intoxication.

PURPOSE: The authors' laboratory has previously documented formate-induced retinal toxicity in a rodent model of methanol intoxication. These studies determined functional, bioenergetic, and structural recovery of the retina after methanol intoxication. METHODS: Rats were intoxicated with methanol, and retinal function was assessed by electroretinography 72 hours after the initial dose of methanol and after a 72-hour recovery period. Retinal energy metabolites, glutathione (GSH) concentrations, and histology were determined at the same time points. RESULTS: Both rod-dominated and UV-cone-mediated electroretinogram responses were profoundly attenuated in methanol-intoxicated rats. In rats allowed to recover from methanol intoxication, there was significant, although incomplete, recovery of rod-dominated retinal function. However, there was no demonstrable improvement in UV-cone-mediated responses. Retinal adenosine triphosphate (ATP), adenosine diphosphate (ADP), and GSH concentrations were significantly reduced after intoxication. Although retinal energy metabolites returned to control values after the recovery period, retinal GSH remained significantly depleted. Histopathologic changes were apparent in the photoreceptors after methanol intoxication, with evidence of inner segment swelling and mitochondrial disruption. In animals allowed to recover from methanol intoxication, there was no evidence of histopathology at the light microscopic level; however, ultrastructural studies revealed subtle photoreceptor mitochondrial alterations. CONCLUSIONS: These findings support the hypothesis that formate inhibits retinal mitochondrial function and increases oxidative stress. They also provide evidence for a differential sensitivity of photoreceptors to the cytotoxic actions of formic acid, with a partial recovery of rod-dominated responses and no recovery of UV-cone-mediated responses.

Increased mitochondrial K(ATP) channel activity during chronic myocardial hypoxia: is cardioprotection mediated by improved bioenergetics?

Increased resistance to myocardial ischemia in chronically hypoxic immature rabbit hearts is associated with activation of ATP-sensitive K(+) (K(ATP)) channels. We determined whether chronic hypoxia from birth alters the function of the mitochondrial K(ATP) channel. The K(ATP) channel opener bimakalim (1 micromol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (FIO(2)=0.21) hearts to values (42+/-4% to 67+/-5% ) not different from those of hypoxic controls but did not alter postischemic recovery of developed pressure in isolated chronically hypoxic (FIO(2)=0.12) hearts (69+/-5% to 72+/-5%). Conversely, the K(ATP) channel blockers glibenclamide (1 micromol/L) and 5-hydroxydecanoate (5-HD, 300 micromol/L) attenuated the cardioprotective effect of hypoxia but had no effect on postischemic recovery of function in normoxic hearts. ATP synthesis rates in hypoxic heart mitochondria (3.92+/-0.23 micromol ATP. min(-1). mg mitochondrial protein(-1)) were significantly greater than rates in normoxic hearts (2.95+/-0.08 micromol ATP. min(-1). mg mitochondrial protein(-1)). Bimakalim (1 micromol/L) decreased the rate of ATP synthesis in normoxic heart mitochondria consistent with mitochondrial K(ATP) channel activation and mitochondrial depolarization. The effect of bimakalim on ATP synthesis was antagonized by the K(ATP) channel blockers glibenclamide (1 micromol/L) and 5-HD (300 micromol/L) in normoxic heart mitochondria, whereas glibenclamide and 5-HD alone had no effect. In hypoxic heart mitochondria, the rate of ATP synthesis was not affected by bimakalim but was attenuated by glibenclamide and 5-HD. We conclude that mitochondrial K(ATP) channels are activated in chronically hypoxic rabbit hearts and implicate activation of this channel in the improved mitochondrial bioenergetics and cardioprotection observed.

Development and characterization of a rodent model of methanol-induced retinal and optic nerve toxicity.

Methanol is an important public health and environmental concern because of the selective actions of its neurotoxic metabolite, formic acid, on the retina, optic nerve and central nervous system. Humans and non-human primates are uniquely sensitive to methanol-induced neurotoxicity as a consequence of the limited capacity of primate species to oxidize and thus detoxify formic acid. The toxic syndrome in primates is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are normally resistant to the accumulation of formate and associated metabolic and visual toxicity. We have characterized retinal and optic nerve toxicity in a nonprimate model of methanol toxicity using rats in which folate-dependent formate oxidation has been selectively inhibited, allowing formate to accumulate to toxic concentrations following methanol administration. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity analogous to the human methanol poisoning syndrome. Visual dysfunction was manifested as reductions in the electroretinogram and the flash-evoked cortical potential which occurred coincident with blood formate accumulation. Histological studies revealed mitochondrial disruption and vacuolation in the retinal pigment epithelium, photoreceptor inner segments and optic nerve. The temporal relationship between methanol administration and the onset and development of ocular toxicity, as well as, the degree of metabolic acidosis and extent of formic acidemia in this rodent model are remarkably similar to that documented in human methanol intoxication. Moreover, the functional and morphologic findings in methanol-intoxicated rats are consistent with the hypothesis that formate acts as a mitochondrial toxin in the retina and optic nerve. The establishment and characterization of this nonprimate animal model of methanol intoxication will facilitate research into the mechanistic aspects of methanol toxicity and the development and testing of treatments for human methanol poisoning.

Alpha-1 adrenoceptor blockade: potential new treatment for anal fissures.

PURPOSE: Patients with chronic anal fissures are known to have high resting anal pressures that return to normal after successful surgical treatment. Internal anal sphincter activity is increased by sympathetic excitatory innervation via alpha adrenoceptors. The objective of this study was to determine the effect of alpha-1 adrenoceptor blockade on anal sphincter pressure in patients with and without chronic anal fissures. METHODS: The effect on the anal canal pressure profile of a single oral 20 mg dose of indoramin, an alpha-1 adrenoceptor antagonist, on seven patients with chronic anal fissure and six healthy patients without a fissure was investigated. RESULTS: Indoramin reduced anal resting pressures in those with anal fissure by a mean of 35.8 percent, from 106.9 +/- 22.15 cm H2O to 68.6 +/- 20.35 cm H2O, and in those without anal fissure by a mean of 39.9 percent, from 84.17 +/- 27.46 cm H2O to 52.17 +/- 24.78 cm H2O, after one hour. This pressure reduction persisted at three hours, and its magnitude is comparable to that obtained after internal sphincterotomy. The pressure reduction occurred over the whole length of the anal canal. CONCLUSION: It is proposed that alpha-1 adrenoceptor antagonists could be a suitable treatment for chronic anal fissure and other painful conditions where reduction in anal pressure is warranted.

Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in preservation of mitochondrial function.

We examined the role of the sarcolemmal and mitochondrial K(ATP) channels in a rat model of ischemic preconditioning (IPC). Infarct size was expressed as a percentage of the area at risk (IS/AAR). IPC significantly reduced infarct size (7 +/- 1%) versus control (56 +/- 1%). The sarcolemmal K(ATP) channel-selective antagonist HMR-1098 administered before IPC did not significantly attenuate cardioprotection. However, pretreatment with the mitochondrial K(ATP) channel-selective antagonist 5-hydroxydecanoic acid (5-HD) 5 min before IPC partially abolished cardioprotection (40 +/- 1%). Diazoxide (10 mg/kg iv) also reduced IS/AAR (36.2 +/- 4.8%), but this effect was abolished by 5-HD. As an index of mitochondrial bioenergetic function, the rate of ATP synthesis in the AAR was examined. Untreated animals synthesized ATP at 2.12 +/- 0.30 micromol x min(-1) x mg mitochondrial protein(-1). Rats subjected to ischemia-reperfusion synthesized ATP at 0.67 +/- 0.06 micromol x min(-1) x mg mitochondrial protein(-1). IPC significantly increased ATP synthesis to 1.86 +/- 0.23 micromol x min(-1) x mg mitochondrial protein(-1). However, when 5-HD was administered before IPC, the preservation of ATP synthesis was attenuated (1.18 +/- 0.15 micromol x min(-1) x mg mitochondrial protein(-1)). These data are consistent with the notion that inhibition of mitochondrial K(ATP) channels attenuates IPC by reducing IPC-induced protection of mitochondrial function.

In vitro susceptibility to pexiganan of bacteria isolated from infected diabetic foot ulcers.

During two clinical trials involving the treatment of 835 outpatients with infected diabetic foot ulcers, 2515 bacterial isolates, including 2337 aerobes and 178 anaerobes, were grown from cultures of the ulcers. The in vitro susceptibility of these isolates was determined to pexiganan, a peptide anti-infective evaluated in these clinical trials, and to other classes of antibiotics. Pexiganan demonstrated broad spectrum antimicrobial activity against Gram-positive and Gram-negative aerobes and anaerobes. The MIC90 values for the most common species among 1735 Gram-positive aerobes isolated, such as Staphylococcus aureus, coagulase-negative staphylococci, Group A streptococci, and Group B streptococci, were 16 micrograms/mL or less. Of 602 Gram-negative aerobes tested, the MIC90 values for pexiganan were 16 micrograms/mL or less for Acinetobacter, Pseudomonas, Stenotrophomonas, Citrobacter, Enterobacter, Escherichia, Klebsiella, and Flavobacterium species. Pexiganan had a MIC90 of 4 to 16 micrograms/mL against the anaerobic isolates of Bacteroides, Peptostreptococcus, Clostridium, and Prevotella species. Importantly, pexiganan did not exhibit cross-resistance with other commonly used antibiotics, including beta-lactams, quinolones, macrolides, and lincosamides. The broad spectrum in vitro antimicrobial activity of pexiganan against clinical isolates from infected diabetic foot ulcers supports its potential as a local therapy for infected diabetic foot ulcers.

Formate-induced inhibition of photoreceptor function in methanol intoxication.

Formic acid is the toxic metabolite responsible for the retinal and optic nerve toxicity produced in methanol intoxication. Previous studies in our laboratory have documented formate-induced retinal dysfunction and histopathology in a rodent model of methanol intoxication. The present studies define the time and concentration dependence of formate-induced retinal toxicity in methanol-intoxicated rats. Retinal function was assessed 24, 48, and 72 h after the initial dose of methanol by flicker electroretinographic measurements. Retinal histopathology was assessed at the same time intervals. Rod- and cone-mediated electroretinogram (ERG) responses were attenuated in a formate concentration- and time-dependent manner, and both retinal sensitivity and maximal responsiveness to light were diminished. Attenuation of UV-cone-mediated responses was temporally delayed in comparison to the functional deficits observed in the 15 Hz/510 nm responses, which have a rod-mediated component and occurred at significantly higher formate concentrations. Both 15 Hz/510 nm and UV-cone-mediated ERG responses were undetectable by 72 h; however, if light intensity was increased, a retinal ERG response could be recorded, indicating that photoreceptor function was profoundly attenuated, but not abolished, under these intoxication conditions. Functional changes preceded structural alterations. Histopathological changes were most pronounced in the outer retina with evidence of inner segment swelling, photoreceptor mitochondrial disruption, and the appearance of fragmented photoreceptor nuclei in the outer nuclear layer. The nature of both the functional and structural alterations observed are consistent with formate-induced inhibition of mitochondrial energy production, resulting in photoreceptor dysfunction and pathology.

Radiographic evidence of silicosis risk in the diatomaceous earth industry.

There is limited and conflicting evidence regarding the exposure-response relationship between exposure to crystalline silica and silicosis; the level of risk to current workers remains uncertain. We conducted an epidemiologic investigation of 1,809 workers in the diatomaceous earth industry, where exposures to crystalline silica are primarily to the cristobalite form. On the basis of the median of three independent readings, 81 (4.5%) workers were judged to have opacities on chest radiographs (small opacities, profusion >= 1/0, and/or large opacities). Age-adjusted relative risk of opacities increased significantly with cumulative exposure to crystalline silica. The concentration of respirable crystalline silica to which workers were exposed (highly correlated with period of hire) was an important determinant of risk after accounting for cumulative exposure. For workers with an average exposure to crystalline silica of <= 0.50 mg/m3 (or hired >= 1950), the cumulative risk of opacities for a cumulative exposure to crystalline silica of 2.0 mg/m3-yr was approximately 1.1%; for an average exposure > 0.50 mg/m3 (or hired < 1950), the corresponding cumulative risk was 3.7%. These findings indicate an exposure-response relationship between cumulative exposure to crystalline silica and radiographic opacities; moreover, the relationship was substantially steeper among workers exposed at the highest average concentrations of crystalline silica.

Very-low-birthweight infants at seven years: an assessment of the health and neurodevelopmental risk conveyed by chronic lung disease.

To determine whether history of chronic lung disease (CLD) in children born at very low birthweight (VLBW) confers additional risk for impaired health, growth, and neurodevelopment, 17 VLBW children born in 1984 who had CLD (requiring supplemental oxygen more than 30 days after birth) in infancy and 28 VLBW children who did not have CLD were assessed at age 7 years. Assessments included a medical history, standard physical and neurological examinations, pulmonary-function tests, and tests of neuropsychological and psychoeducational functioning. Health status did not differ between the groups. In contrast, children with CLD did not perform as well in neuropsychological and psychoeducational assessments. Although CLD confers little added risk to health, it seems to add significantly to risks for poor school performance that are known to be associated with very low birthweight.

Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). DESIGN: Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. SETTING: University hospital clinical research unit. PATIENTS: Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15). INTERVENTIONS: Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. MEASUREMENTS AND MAIN RESULTS: After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. CONCLUSIONS: Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.

Paradoxical puborectalis contraction is a feature of constipation in patients with multiple sclerosis.

OBJECTIVE: To study the disturbed anorectal physiology associated with constipation in multiple sclerosis. METHODS: Anorectal function in 10 patients with clinically definite multiple sclerosis and constipation has been compared with 10 normal persons and 11 patients with idiopathic constipation, without multiple sclerosis. RESULTS: All 10 constipated patients with multiple sclerosis had difficulty evacuating barium paste during defaecography. In four of these there was complete failure of puborectalis relaxation when straining to defaecate, and in another four there was incomplete puborectalis relaxation. There was no evidence of lower motor neuron involvement of pelvic floor muscles in the multiple sclerosis group. CONCLUSIONS: Paradoxical puborectalis contraction is common in patients with multiple sclerosis in whom constipation is a symptom. This may be a feature of the disturbed voluntary sphincter control mechanism, analogous to detrusor sphincter dyssnergia in the bladder.

Nasal lavage cytokines in normal, allergic, and asthmatic school-age children.

Inflammation can be demonstrated in the airway mucosa of asthmatics, even in the absence of overt symptoms, but the pathogenesis of this chronic inflammation is incompletely defined. It has been suggested that inflammatory cytokines produced by epithelium may play important roles in this process. Therefore, we measured the cytokines interleukin-8 (IL-8), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in nasal lavage fluids from school-age children who were (1) "normal" (nonallergic/nonasthmatic), (2) allergic to house-dust mite antigen but nonasthmatic (no history of wheezing), or (3) allergic and asthmatic (history of > or = 10 wheezing episodes). Children underwent a single nasal lavage procedure while asymptomatic and on no anti-inflammatory medications or anti-histamines. In addition to cytokine concentrations, cell counts, differentials, albumin, histamine, and eosinophil cationic protein (ECP) concentrations were determined in nasal lavage fluids. Significant increases in IL-8 and ECP were observed in asthmatics compared with both normals and allergic nonasthmatics. Overall, IL-8 in nasal lavage fluids correlated significantly with ECP. Allergic nonasthmatics did not have significant increases in cytokines or other mediators compared with normal subjects. Concentrations of IL-6 did not differ significantly among the three groups, and GM-CSF was undetectable in all samples tested. We conclude that increased IL-8 production and eosinophil activation are characteristic of the airways of asthmatic children when asymptomatic, and we speculate that IL-8 plays a role in the maintenance of airway inflammation in asthma.

The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats.

PURPOSE: This study was conducted to determine the potential influence of PaO2 fluctuation on the retinal neovascular response known to occur in newborn rats exposed to hyperoxic conditions. As an inherent corollary, the authors also defined the relationship between the fraction of inspired oxygen (FiO2) and the arterial blood oxygen tension (PaO2) in newborn rats. METHODS: Experiment 1 was composed of several oxygen-exposure protocols in which atmospheres of 10% oxygen concentration were alternated with different higher levels of ambient oxygen (50%, 40%, 30%, and room air). In experiment 2, two alternating oxygen concentrations were made to converge toward room air (20.9% oxygen) with each successive group of four treatment groups. These included another group exposed to alternating 50% and 10% oxygen, a group exposed to alternating 45% and 12.5% oxygen concentrations, one exposed to alternating concentrations of 40% and 15% oxygen, and a final group exposed to 35% and room air oxygen concentrations. In each case, oxygen was alternated between the two exposure concentrations every 24 hours. The term delta FiO2 is used to designate the difference in the two oxygen concentrations to which a treatment group was subjected, applying the units of fraction of inspired oxygen (i.e., delta FiO2 = 0.4 for the exposure to alternating 50% and 10% oxygen). At birth, litters of albino rats were placed in each of these environments for 13 or 14 days, after which PaO2 and retinal vascular development were assessed in some rats. The remainder were removed to room air for 4 days before the incidence and severity of abnormal neovascularization were measured. RESULTS: PaO2 and FiO2 were directly and linearly correlated (r2 = 0.998). In experiment 1, the extent of retinal vascular development on removal from oxygen was a linear function of delta FiO2. Retinal neovascularization subsequently occurred in all rats exposed to alternating 50% and 10% or 40% and 10% oxygen concentrations, but only a third of the 30% and 10% exposure group, indicating a minimum threshold for proliferative disease at delta FiO2 = 0.2. In experiment 2, retinal avascularity also increased linearly with increasing delta FiO2. There was a threshold for neovascularization between the exposure to alternating 45% and 12.5% oxygen and the 40% and 15% oxygen exposure (100% versus 4.8% incidence of neovascularization), indicating a requirement of < or = 12.5% oxygen episodes to stimulate a consistent proliferative response. CONCLUSIONS: These results suggest that PaO2 fluctuation and degree of hypoxia may have more influence on proliferative retinal disease in newborn rats than the extended hyperoxia that has historically received greater attention. Experimental designs that address the inherent differences in pulmonary function between intrinsically healthy animals and compromised premature infants are of substantial value to our understanding of the pathogenesis of retinopathy of prematurity.

Correlates of recurrent wheezing in school-age children. The Physicians of Raleigh Pediatric Associates.

Correlates of recurrent wheezing were examined in a case-control study involving 343 children ranging from 7 to 12 yr of age and recruited from a general pediatric practice. Positive skin tests for allergy were observed in 35% of a random sample of children without recurrent wheezing, and in 77% and 90% of children who had experienced from two to four episodes and five or more episodes, respectively, of recent wheezing. By logistic regression analysis, sensitization to dust mite (odds ratio [OR]: 5.2; 95% CI: 3.0 to 9.0), cat (OR: 15.5; 95% CI: 3.4 to 70.8), and Alternaria (OR: 6.8; 95% CI: 2.1 to 21.5) antigens was consistently associated with recurrent wheezing. Sensitization to pollen antigen(s), observed in 60% of allergic children, was not associated with wheezing. A family history of asthma was a significant predictor of recurrent wheezing (OR: 3.2; 95% CI: 1.7 to 5.9) after adjusting for its association with positive skin tests. Environmental tobacco smoke (ETS) exposure was associated with an increased risk of recurrent wheezing in nonallergic children and in allergic females, but not in allergic males. ETS exposure was not associated with positive skin tests for allergy. A history of wheezing with respiratory illness before 2 yr of age was associated with a modest risk of recurrent wheezing between 7 and 12 yr of age (OR: 2.3; 95% CI: 1.2 to 4.6), a risk that did not differ by allergic status or gender. Theoretically, the prevalence of recurrent wheezing in this population could be reduced approximately 65% by controlling exposure to indoor allergens and ETS.

Abnormal internal anal sphincter fibrosis and elasticity in fecal incontinence.

PURPOSE: We aimed to investigate the changes in the proportion of collagen and in the elasticity of the internal anal sphincter in patients with neurogenic fecal incontinence. METHODS: Collagen content was studied in ten patients with neurogenic fecal incontinence (mean age, 51.5 years) and ten controls (age, 58.6 years) using histologic techniques to determine differences between incontinence and health and to determine the effect of aging. Changes in elasticity were also measured in 8 controls (mean age, 63 years) and 13 patients with neurogenic incontinence (mean age, 60 years) by recording the in vitro length-tension relationship of the freshly excised internal anal sphincter. RESULTS: Incontinent patients had a significantly higher collagen content than controls (55 percent vs. 33 percent; P = 0.013). In incontinent patients the amount of collagen and the patients' ages correlated significantly (P = 0.001). There was a greater increase in stable tension per increase in muscle length in the strips from incontinent patients compared with controls. CONCLUSIONS: Changes in fibrous tissue content are likely to influence muscle tone and responsiveness of the sphincter in fecal incontinence.