Sex-specific lung inflammation and mitochondrial damage in a model of electronic cigarette exposure in asthma.

The prevalence of electronic cigarette (EC) use among adult with asthma has continued to increase over time, in part due to the belief of being less harmful than smoking. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. In the present project, we tested the hypothesis that EC use contributes to respiratory damage and worsening inflammation in the lungs of patients with asthma. To define the consequences of EC exposure in established asthma, we used a mouse model with/without preexisting asthma for short-term exposure to EC aerosols. C57/BL6J mice were sensitized and challenged with a DRA (dust mite, ragweed, Aspergillus fumigates, 200 µg/mL) mixture and exposed daily to EC with nicotine (2% nicotine in 30:70 propylene glycol: vegetable glycerin) or filtered air for 2 wk. The mice were evaluated at 24 h after the final EC exposure. After EC exposure in asthmatic mice, lung inflammatory cell infiltration and goblet cell hyperplasia were increased, whereas EC alone did not cause airway inflammation. Our data also show that mitochondrial DNA (mtDNA) content and a key mtDNA regulator, mitochondrial transcription factor A (TFAM), are reduced in asthmatic EC-exposed mice in a sex-dependent manner. Together, these results indicate that TFAM loss in lung epithelium following EC contributes to male-predominant sex pathological differences, including mitochondrial damage, inflammation, and remodeling in asthmatic airways.NEW & NOTEWORTHY Respiratory immunity is dysregulated in preexisting asthma, and further perturbations by EC use could exacerbate asthma severity. However, the extent of their toxicity and the involved mechanisms contributing to the deleterious impact of EC exposure on patients with preexisting asthma have not been delineated. We found that EC has unique biological impacts in lungs and potential sex differences with loss of TFAM, a key mtDNA regulator, in lung epithelial region from our animal EC study.

In Utero Exposure to Maternal Electronic Nicotine Delivery System use Demonstrate Alterations to Craniofacial Development.

OBJECTIVE: Develop a model for the study of Electronic Nicotine Device (ENDS) exposure on craniofacial development. DESIGN: Experimental preclinical design followed as pregnant murine dams were randomized and exposed to filtered air exposure, carrier exposure consisting of 50% volume of propylene glycol and vegetable glycine (ENDS Carrier) respectively, or carrier exposure with 20 mg/ml of nicotine added to the liquid vaporizer (ENDS carrier with nicotine). SETTING: Preclinical murine model exposure using the SciReq exposure system. PARTICIPANTS: C57BL6 adult 8 week old female pregnant mice and exposed in utero litters. INTERVENTIONS: Exposure to control filtered air, ENDS carrier or ENDS carrier with nicotine added throughout gestation at 1 puff/minute, 4 h/day, five days a week. MAIN OUTCOME MEASURES: Cephalometric measures of post-natal day 15 pups born as exposed litters. RESULTS: Data suggests alterations to several facial morphology parameters in the developing offspring, suggesting electronic nicotine device systems may alter facial growth if used during pregnancy. CONCLUSIONS: Future research should concentrate on varied formulations and exposure regimens of ENDS to determine timing windows of exposures and ENDS formulations that may be harmful to craniofacial development.

E-cigarette vapor exposure in utero causes long-term pulmonary effects in offspring.

The in utero environment is sensitive to toxicant exposure, altering the health and growth of the fetus, and thus sensitive to contaminant exposure. Though recent clinical data suggest that e-cigarette use does no further harm to birth outcomes than a nicotine patch, this does not account for the effects of vaping during pregnancy on the long-term health of offspring. Pregnant mice were exposed to: 1) e-cigarette vapor with nicotine (PV + Nic; 2% Nic in 50:50 propylene glycol: vegetable glycerin), 2) e-cigarette vapor without nicotine [PV; (50:50 propylene glycol:vegetable glycerin)], or 3) HEPA filtered air (FA). Dams were removed from exposure upon giving birth. At 5 mo of age, pulmonary function tests on the offspring revealed female and male mice from the PV group had greater lung stiffness (Ers) and alveolar stiffness (H) compared with the FA group. Furthermore, baseline compliance (Crs) was reduced in female mice from the PV group and in male mice from the PV and PV + Nic groups. Lastly, female mice had decreased forced expiratory volume (FEV0.1) in the PV group, but not in the male groups, compared with the FA group. Lung histology revealed increased collagen deposition around the vessels/airways and in alveolar tissue in PV and PV + Nic groups. Furthermore, goblet hyperplasia was observed in PV male and PV/PV + Nic female mice. Our work shows that in utero exposure to e-cigarette vapor, regardless of nicotine presence, causes lung dysfunction and structural impairments that persist in the offspring to adulthood.

Short-term PM exposure and social stress cause pulmonary and cardiac dysfunction.

Ambient particulate matter (PM) exposure increases risk for cardiopulmonary health problems which may be exacerbated in a stressful environment. Co-exposure to PM and stress characterizes the experience of many deployed military personnel and first responders but has not been thoroughly investigated. This is especially relevant to military personnel who have been exposed to high PM levels in conjunction with stressful military conflict situations. To understand the mechanisms and time-course of the health consequences following burn pit exposure, we exposed mice to moderate levels of ambient PM less than 2.5 µM in diameter (PM2.5) alone or in combination with psychological stress. We found male mice exposed to PM2.5 alone or in combination with stress had significantly reduced pulmonary function when subjected to methacholine, indicating increased airway hyperreactivity. These mice experienced increased goblet cell hyperplasia in their lungs, with no change in alveolar density. Mice exposed to PM2.5 and/or stress also exhibited reduced cardiac contractility, right ventricular (RV) output, and changes in RV capillary density and cardiac inflammatory markers. Taken together, these data indicate that short-term exposure to PM2.5 with or without stress causes a clear reduction in pulmonary and cardiac function. We believe that this model is well-suited for the study of military and other occupational exposures, and future work will identify potential mechanisms, including the inflammatory progression of these co-exposures.

Performance on a modified signal detection task of attention is impaired in male and female rats following developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate.

Based on evidence that the developing mesocortical dopamine pathway is sensitive to progestins, in the present study we tested the hypothesis that attention, a fundamental component of successful cognitive behavior, is disrupted by developmental exposure to the synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC). To assess attentional impairments, a modified signal detection task was utilized with three stimulus modalities: compound (light and tone), light alone, and tone alone, for four stimulus durations (2, 0.5, 0.25, 0.125 s). Adult rats were trained to push one lever if they detected the stimulus, and another lever if the stimulus was not presented. 17-OHPC animals were able to attend to the task, as evidenced by similar correct responses as controls. However, as the task became increasingly difficult at shorter durations, 17-OHPC animals made significantly more omissions compared to controls, suggesting that 17-OHPC treatment may disrupt attentional processes and/or delay response time. These findings add to the current body of literature demonstrating that exposure to 17-OHPC during development produces deficits in cognitive behavior in adulthood. These results may inform potential risks associated with 17-OHPC treatment in pregnant women with a history of preterm delivery who are commonly recipients of such treatment.

Primary Malignant Melanoma of the Urinary Bladder.

There are only 30 reported cases of primary malignant melanoma of the bladder in the literature so far. Of those, 17 cases were reported as deceased within three years of presentation. Our case reported here is that of a 78-year-old female who presented with a new-onset incontinence and intermittent hematuria. She had no evidence of primary melanoma anywhere else in her body. The patient was treated with cystectomy and ileal conduit with plans for adjuvant chemotherapy. Unfortunately, the patient succumbed to her disease with diffuse metastatic involvement within 16 months of presentation.

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the ß-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression.

Aneusomy detected by fluorescence in-situ hybridization has high positive predictive value for Barrett's dysplasia.

AIMS: The goal of this study was to pilot a commercial four-colour fluorescence in-situ hybridization (FISH) probe set as a marker of dysplasia in surveillance biopsies. METHODS AND RESULTS: FISH probes to 9p12 (CDKN2A), 17q11.2-12 (HER2), 8q24.12-13 (CMYC) and 20q13.2 (ZNF217) in 20 cases of Barrett's oesophagus. Dysplastic and non-dysplastic mucosa were compared for each case. Two observers independently counted 50 cells in each region of interest (ROI), and the mean score taken. Wilcoxon's signed-rank test was used to determine the significance of differences between dysplastic and non-dysplastic tissue. Predictive power was determined by logistic regression and receiver operator characteristic (ROC) curves were plotted to examine sensitivity and specificity of each gene to detect dysplasia. Interobserver agreement was excellent. HER2, CMYC and ZNF217 showed significant (P < 0.0005) increases in copy number in dysplastic mucosa; CDKN2A had an insignificant (P = 0.852) decrease when compared to non-dysplastic mucosa. While aneusomy was strongly predictive of dysplasia, eusomy did not rule it out. CONCLUSIONS: Increased HER2, CMYC and ZNF217 copy number distinguished dysplastic from non-dysplastic mucosa, but non-detection of aneusomy did not exclude dysplasia. Further studies are justified to determine whether FISH-positive dysplasia might justify earlier treatment by radio-frequency ablation.

TRAM flap versus nonautologous breast reconstruction: what do patients really think?

Although there have been many reports of aesthetic outcomes after breast reconstruction, there have been comparatively few studies examining patient satisfaction and related subjective issues. The variables affecting satisfaction are only beginning to be understood, and patient satisfaction issues were explored in a more homogeneous patient population. A questionnaire surveying overall and aesthetic satisfaction, postoperative recuperation time, and symptoms was used to elicit candid patient responses. Fifty-seven patients replied (86 percent response rate), of whom 38 had undergone transverse rectus abdominis musculocutaneous (TRAM) flap (pedicled, n = 29; free, n = 9) reconstruction and 19 had undergone nonautologous reconstruction. Although the median patient satisfaction score was higher for the TRAM flap group, this was not statistically significant (p = 0.92). Recuperation was significantly longer for the TRAM flap group, with only 47 percent of patients being able to resume full activities within 2 months after the surgical procedure, compared with 95 percent of the implant group (p = 0.002). Of the TRAM flap-treated patients, 50 percent described some postoperative abdominal weakness, but only 5 percent of all TRAM flap-treated patients said that abdominal weakness was actually a functional problem. Our results suggest that patients may derive equal satisfaction with the two methods of reconstruction. The postoperative recuperation time after TRAM flap reconstruction is significantly longer than that after nonautologous procedures, although the postoperative abdominal weakness after TRAM flap reconstruction is not as significant a clinical problem as previously thought. The patient-derived information on satisfaction should assist both surgeons and patients in matching reconstructive options with patients' expectations and lifestyle.

Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies.

Three Cannabis Based Medicinal Extracts (CBMEs) for sublingual use became available in 2000. A total of 34 'N of 1' studies were undertaken using this novel therapy for patients with chronic, mainly neuropathic, pain and associated symptoms to explore efficacy, tolerability, safety and dosages. Three CBMEs (Delta9 Tetrahydrocannabinol (THC), Cannabidiol (CBD) and a 1:1 mixture of them both) were given over a 12-week period. After an initial open-label period, the CBMEs were used in a randomised, double-blind, placebo controlled, crossover trial. Extracts which contained THC proved most effective in symptom control. Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed. Side-effects were common, reflecting a learning curve for both patient and study team. These were generally acceptable and little different to those seen when other psycho-active agents are used for chronic pain. These initial experiences with CBME open the way to more detailed and extensive studies.

Tasas estimadas de mortalidad infantil, cobertura de vacunación y uso de sales de rehidratación en Guatemala: variaciones según distintas fuentes / Variations in estimates of guatemalan infant mortality, vaccination coverage, and rehydration salts use reported by different sources

Se buscaron e investigaron todas las tasas estimativas de mortalidad infantil, cobertura por vacunación ( con la vacuna BCG, tres dosis de las vacunas DTP y antipoliomielítica, vacuna antisarampionosa y toxoide tetánico) y uso de sales de rehidratación oral (SRO) en Guatemala en el decenio de 1980. Se encontraron muchas fuentes y estimaciones, así como grandes discrepancias entre las estimaciones de un mismo indicador, aun tratándose de estimaciones para el mismo año procedentes de la misma fuente. Por ejemplo, los informes correspondientes a 1985 dieron 10 estimaciones distintas de la tasa de mortalidad infantil, que varió de 56,0 a 79,8 defunciones por 1000 niños nacidos vivos; estimaciones de cobertura de 30 a 60, 5 por ciento con la vacuna BCG, de 3,5 a 34,2 por ciento con las tres dosis de vacuna DPT, de 3,5 a 33,5 por ciento con las tres dosis de vacuna antipoliomielítica, de 11 a 58,2 por ciento con la vacuna antisarampionosa y de 1 a 8,2 por ciento con el toxoide tetánico; y tasas estimadas de uso de SRO que fluctuaron de 3,5 a 7,2 por ciento. Asimismo, tres estimaciones del número de defunciones infantiles por 1000 nacidos vivos en 1984 procedentes del Ministerio de Salud Pública y Asistencia Social de Guatemala variaron de 52,4 a 79,8; cuatro del Fondo de las Naciones Unidas para la Infancia correspondientes a 1985, de 65 a 79,8; y tres de la Agencia de los Estados Unidos para el Desarrollo Internacional correspondientes a 1987, de 59 a 72. Las principales razones de esa diversidad apuntan graves problemas que restan fiabilidad a los datos existentes

Variations in estimates of Guatemalan infant mortality, vaccination coverage, and ORS use reported by different resources

All available estimates of rates of infant mortality, vaccination coverage (for BCG, DPT 3, polio 3, measles, and tetanus toxoid), and ORS use in Guatemala in the 1980s were identified and investigated. A large number of sources and estimates were found. Large discrepancies were also found between the estimates for a given indicator, even when the estimates were reported for the same year by the same source. For instance, reports for 1985 yielded 10 different infant mortality estimates ranging from 56.0 to 79.8 deaths per 1 000 live births; vaccination coverage estimates ranging from 30 percent to 60.5 percent for BCG, 3.5 percent to 34.2 percent for DPT 3,3.5 percent for polio 3,11 percent to 58.2 percent for measles, and 1 percent to 8.2 percent for tetanus toxoid; and estimated use rates of oral rehydration solution ranging from 3.5 percent to 7.2 percent. In this same vein, three Guatemalan Ministry of Health estimates of infant deaths per 1 000 live births in 1984 ranged from 52.4 to 79.8; four UNICEF estimates for 1985 ranged from 65 to 79.8; and three USAID estimates for 1987 ranged from 58 to 72. The many reasons found for this diversity point to significant problems influencing the reliability of current data

Tasas estimadas de mortalidad infantil, cobertura de vacunación y uso de sales de rehidratación en Guatemala: variaciones según distintas fuentes / Variations in estimates of guatemalan infant mortality, vaccination coverage, and rehydration salts use reported by different sources

Se buscaron e investigaron todas las tasas estimativas de mortalidad infantil, cobertura por vacunación ( con la vacuna BCG, tres dosis de las vacunas DTP y antipoliomielítica, vacuna antisarampionosa y toxoide tetánico) y uso de sales de rehidratación oral (SRO) en Guatemala en el decenio de 1980. Se encontraron muchas fuentes y estimaciones, así como grandes discrepancias entre las estimaciones de un mismo indicador, aun tratándose de estimaciones para el mismo año procedentes de la misma fuente. Por ejemplo, los informes correspondientes a 1985 dieron 10 estimaciones distintas de la tasa de mortalidad infantil, que varió de 56,0 a 79,8 defunciones por 1000 niños nacidos vivos; estimaciones de cobertura de 30 a 60, 5 por ciento con la vacuna BCG, de 3,5 a 34,2 por ciento con las tres dosis de vacuna DPT, de 3,5 a 33,5 por ciento con las tres dosis de vacuna antipoliomielítica, de 11 a 58,2 por ciento con la vacuna antisarampionosa y de 1 a 8,2 por ciento con el toxoide tetánico; y tasas estimadas de uso de SRO que fluctuaron de 3,5 a 7,2 por ciento. Asimismo, tres estimaciones del número de defunciones infantiles por 1000 nacidos vivos en 1984 procedentes del Ministerio de Salud Pública y Asistencia Social de Guatemala variaron de 52,4 a 79,8; cuatro del Fondo de las Naciones Unidas para la Infancia correspondientes a 1985, de 65 a 79,8; y tres de la Agencia de los Estados Unidos para el Desarrollo Internacional correspondientes a 1987, de 59 a 72. Las principales razones de esa diversidad apuntan graves problemas que restan fiabilidad a los datos existentes

Se publica en inglés en Bull. PAHO Vol. 29(1), 1995

Variations in estimates of Guatemalan infant mortality, vaccination coverage, and ORS use reported by different resources

All available estimates of rates of infant mortality, vaccination coverage (for BCG, DPT 3, polio 3, measles, and tetanus toxoid), and ORS use in Guatemala in the 1980s were identified and investigated. A large number of sources and estimates were found. Large discrepancies were also found between the estimates for a given indicator, even when the estimates were reported for the same year by the same source. For instance, reports for 1985 yielded 10 different infant mortality estimates ranging from 56.0 to 79.8 deaths per 1 000 live births; vaccination coverage estimates ranging from 30 percent to 60.5 percent for BCG, 3.5 percent to 34.2 percent for DPT 3,3.5 percent for polio 3,11 percent to 58.2 percent for measles, and 1 percent to 8.2 percent for tetanus toxoid; and estimated use rates of oral rehydration solution ranging from 3.5 percent to 7.2 percent. In this same vein, three Guatemalan Ministry of Health estimates of infant deaths per 1 000 live births in 1984 ranged from 52.4 to 79.8; four UNICEF estimates for 1985 ranged from 65 to 79.8; and three USAID estimates for 1987 ranged from 58 to 72. The many reasons found for this diversity point to significant problems influencing the reliability of current data

This article will also be published in Spanish in the BOSP. Vol. 118, 1995