Hypokinetic catatonia in an adolescent with psychotic and mood disorders: A case report.

OBJECTIVE: Pediatric catatonia case report and literature review. METHODS: Retrospective chart review and provider consultation. RESULTS: A case of pediatric catatonia is described in the setting of mood and psychotic disorders. Treatment course and outcomes are considered in the context of supporting literature review and discussion. CONCLUSIONS: Pediatric catatonia is a debilitating and at times life threatening condition. Pediatric catatonia is historically underdiagnosed and its clinical presentation may differ from more common adult cases of catatonia. Correct identification, acute treatment, and long-term management is key to optimizing prognosis and patient outcomes.

A cross-sectional study of biomarkers of exposure and effect in smokers and moist snuff consumers.

BACKGROUND: Cigarette smoking is a major risk factor for several chronic diseases. Epidemiological data indicate the use of smokeless tobacco (ST) is associated with significantly lower risk for smoking-related diseases compared to cigarettes. Several biomarkers of exposure (BioExp) and effect (BioEff) associated with smoking and use of moist snuff (ST) were evaluated. METHODS: A single site, cross-sectional clinical study enrolled three groups of generally healthy male smokers (SMK), moist snuff consumers (MSC), and non-tobacco consumers (NTC), and several BioExp and BioEff were evaluated. RESULTS: Blood and urinary BioExp, including total nicotine equivalents and tobacco-specific nitrosamines, were higher in MSC compared to SMK. Biomarkers of combustion-related toxicants and cadmium were elevated in SMK. Elevated levels of some BioEff associated with oxidative stress (urinary isoprostanes and leukotriene E4), inflammation (white blood cell count), platelet activation (thromboxane metabolites), and lipid metabolism (apolipoprotein B100 and oxidized low-density lipoprotein) were observed in SMK relative to NTC and MSC (all p<0.05). The non-smoking groups (MSC and NTC) showed similar levels of combustion-related BioExp and BioEff. CONCLUSIONS: Higher levels of exposure to nicotine and some N'-nitrosamines may be observed in MSC, and SMK are exposed to higher levels of combustion-related toxicants. Changes in BioEff consistent with some aspects of inflammation, oxidative stress, and altered lipid metabolism were detected in SMK compared to the non-smoking groups. The biomarker data further improve our understanding of pathophysiological changes and the risk continuum associated with various tobacco products, and could be useful components of future assessments of tobacco products.

Effects of cigarette smoking on circulating leukocytes and plasma cytokines in monozygotic twins.

BACKGROUND: Despite the well-documented role of cigarette smoke in the development of chronic obstructive pulmonary disease (COPD), lung cancer and cardiovascular disease, biomarkers for screening or monitoring disease progression and outcome remain elusive, particularly for COPD and lung cancer. Inflammatory cells and mediators are likely to be involved in the disease processes, but their importance is still poorly understood. The purpose of this study was to investigate early changes in immunological markers associated with smoking in healthy monozygotic twins without a detectable disease discordant for smoking, thereby minimising data variability due to genetic background. METHODS: Twenty-two monozygotic twin pairs, aged 31.5±6.3 years, entered the study. One of each twin pair was a smoker and the other a non-smoker. None of the subjects reported any diseases or clinically defined respiratory symptoms or airflow limitation. Each subject donated blood samples for determination of total leukocytes and subpopulations, lymphocyte subpopulation plus pro-inflammatory mediators (interleukin-8, tumour necrosis factor-α, soluble tumour necrosis factor-α receptors and C-reactive protein). RESULTS: We observed a significant increase in the number of circulating leukocytes and neutrophils in smokers compared to non-smokers. Smokers also had significantly higher numbers of B cells and CD4+ T cells, plus an increased CD4/CD8 ratio. The numbers of NK cells were statistically significant lower in smokers compared to non-smokers. CONCLUSIONS: While the prognostic significance of these changes is uncertain, results suggest that smoking is associated with immune changes, independent of genetic background and environmental conditions.

A TRP channel in the lysosome regulates large particle phagocytosis via focal exocytosis.

Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+-dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.

Urinary biomarkers of smokers' exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach.

There are established guidelines for bioanalytical assay validation and qualification of biomarkers. In this review, they were applied to a panel of urinary biomarkers of tobacco smoke exposure as part of a "fit for purpose" approach to the assessment of smoke constituents exposure in groups of tobacco product smokers. Clinical studies have allowed the identification of a group of tobacco exposure biomarkers demonstrating a good doseresponse relationship whilst others such as dihydroxybutyl mercapturic acid and 2-carboxy-1-methylethylmercapturic acid - did not reproducibly discriminate smokers and non-smokers. Furthermore, there are currently no agreed common reference standards to measure absolute concentrations and few inter-laboratory trials have been performed to establish consensus values for interim standards. Thus, we also discuss in this review additional requirements for the generation of robust data on urinary biomarkers, including toxicant metabolism and disposition, method validation and qualification for use in tobacco products comparison studies.

Lung cancer biomarkers for the assessment of modified risk tobacco products: an oxidative stress perspective.

Manufacturers have developed prototype cigarettes yielding reduced levels of some tobacco smoke toxicants, when tested using laboratory machine smoking under standardised conditions. For the scientific assessment of modified risk tobacco products, tests that offer objective, reproducible data, which can be obtained in a much shorter time than the requirements of conventional epidemiology are needed. In this review, we consider whether biomarkers of biological effect related to oxidative stress can be used in this role. Based on published data, urinary 8-oxo-7,8-dihydro-2-deoxyguanosine, thymidine glycol, F2-isoprostanes, serum dehydroascorbic acid to ascorbic acid ratio and carotenoid concentrations show promise, while 4-hydroxynonenal requires further qualification.

Cross-sectional study of biomarkers of exposure and biological effect on monozygotic twins discordant for smoking.

BACKGROUND: The aim of this study was to investigate the possible correlation between smoking status and biomarkers of exposure (BoE) and biological effect (BoBE) in monozygotic twins discordant for smoking status (smoker and non-smoker pairs). By eliminating potential genetic variability in this manner, a clearer pattern of the effects of lifestyle and environmental exposures should become apparent. METHODS: This was a cross-sectional study on monozygotic healthy twins (44 subjects, 26 males and 18 females) with a mean age 31.5 years. BoE to cigarette smoke and BoBE were measured in body fluids (24 h urine and blood) after medical pre-screening. RESULTS: All BoE were significantly higher in the smoker twins. Among BoBE, 11-dehydrothromboxane B(2) (11-dehydro TBX), 2,3-dinorthromboxane B(2) (2,3-dinor TBX), 8-epi-prostaglandin F2α (8-epiPGF), hydroxyproline (OH-P), fibrinogen, white blood cell (WBC), neutrophil and lymphocyte counts and heart rate were statistically significantly increased in the smoker compared to the non-smoker twins. Moreover, statistically significant correlations between neutrophil count and 11-dehydro TBX (r=0.32), WBC and 8-epiPGF (r=0.33), OH-P and 8-epiPGF (r=0.49) and heart rate and fibrinogen (r=0.46) were observed. CONCLUSIONS: The study results confirmed the reliability of the BoE for the evaluation of smoking status. Moreover, a subset of the BoBE, reported as being associated with inflammatory conditions and early stages of vascular disorders, has emerged as showing a consistent relationship with smoking status from the present and the previous studies. By using monozygotic twin pairs, genetic variability has been excluded as a possible source of variability in this study. These results should assist in the interpretation of other population studies using these biomarkers.

A cross-sectional investigation of biomarkers of risk after a decade of smoking.

Two groups of 20 healthy volunteers with cigarettes of different tar yield were compared with a group of 20 never smokers over 24 h for several biomarkers. All groups were of similar mean ages and the smokers had smoked for a homogeneous period of approximately 10 yr. The groups were assessed using routine medical parameters as well as biomarkers of recent smoke exposure and other biomarkers that were under evaluation as possible markers of risk for smoking-associated diseases. All biomarkers of exposure-carbon monoxide, nicotine plus its five major metabolites, and 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanol (NNAL)-were significantly elevated in smokers. For biomarkers of potential risk evaluated in the blood, white cells and immunoglobulin (Ig) G showed a decrease related to smoking status (p < .01). Interleukin 6 levels were higher in smoker groups compared to never smokers, with a significant increasing trend across the groups (p < .05). Among the urinary biomarkers studied, 11-deydro-thromboxane B2, 2,3-dinor-thromboxane B2, and thymidine glycol showed significant increasing trends across the groups (p < .01). The results suggest that after the first decade or less of smoking, changes in inflammatory, immunological, and cardiovascular function can be observed. However, further studies on larger groups will be required to better understand the kinetics of these subtle effects observed early in smokers and their relationship with the potential risk of subsequent smoking-associated disease.

Evaluation of biomarkers of exposure and potential harm in smokers, former smokers and never-smokers.

BACKGROUND: The objective of this study was to obtain baseline data on biomarkers of exposure (BoE) and biomarkers of potential harm (BoPH) in smokers, former smokers and never-smokers. METHODS: This was a cross-sectional study of 80 healthy male and female volunteers over 21 years old, self-selected for smoking status. Subjects were prescreened by medical staff at an independent clinical research unit, within 1 week prior to a single overnight residential visit and sample collection. RESULTS: All BoE were able to differentiate between the two smoking groups and smokers from all nonsmokers. There was a strong correlation between cigarettes smoked per day and total urinary nicotine equivalents (TNE; r=0.85). TNE correlated better with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol levels than cigarettes smoked per day (r=0.75 and r=0.56, respectively). Of the BoPH included in this study, seven (11-dehydro-thromboxane B2, 2, 3-dinorthrom-boxane B2, 8-epi prostaglandin F(2alpha), 8-hydroxy-2 deoxyguanosine, cis-thymidine glycol, low-density lipoprotein cholesterol and IgG) were significantly different between the group who smoked more cigarettes per day and never-smokers. These differences became more apparent and extended to the group who smoked 10 or less cigarettes per day, when total urinary recovery values were corrected for creatinine clearance. CONCLUSIONS: While BoE clearly differentiate between groups based on self-declared smoking status, most BoPH examined could not do so in a consistent manner. The dynamics of BoPH levels are not well understood. Future studies of BoPH should eliminate potential confounding factors and increase the number of subjects to allow the investigation of genetic polymorphism in metabolic pathways.

Cardiovascular biomarkers in groups of established smokers after a decade of smoking.

To investigate tools for evaluation of smoking-associated disease initiation and progression, we examined basic clinical parameters and biomarkers of cardiovascular disease risk, in a group of healthy volunteers with an average 10-year smoking history. A small cross-sectional study of never-smokers, moderate smokers and smokers was performed. Caucasians were recruited to match pre-defined cigarette tar yields and cigarettes smoked per day. For haematological parameters, significant differences between never-smokers and all female smokers combined were seen for haemoglobin concentration, haematocrit, total leucocyte count, neutrophil count and lymphocyte count. For all male smokers combined, only total leucocyte count was statistically different. Analysis of exhaled CO and other smoke exposure biomarker (nicotine and its metabolites) data showed a statistically significant increase in all groups of smokers with a trend related to the number of cigarettes smoked per day. Thromboxane urinary metabolites 11-dehydro-thromboxane B(2) and 2,3-dinor-thromboxane B(2) were statistically significantly elevated in smokers. Significant statistical differences between smokers with approximately 10 years of smoking history and non-smokers in white cells count, hemoglobin and thromboxane turnover were seen, although they did not reach levels associated with overt diseases. These data could provide insight into early biomarkers predictive of risk for coronary and vascular disease.