Guideline on multimodal rehabilitation for patients with post-intensive care syndrome.

BACKGROUND: Intensive Care Unit (ICU) survivors often experience several impairments in their physical, cognitive, and psychological health status, which are labeled as post-intensive care syndrome (PICS). The aim of this work is to develop a multidisciplinary and -professional guideline for the rehabilitative therapy of PICS. METHODS: A multidisciplinary/-professional task force of 15 healthcare professionals applied a structured, evidence-based approach to address 10 scientific questions. For each PICO-question (Population, Intervention, Comparison, and Outcome), best available evidence was identified. Recommendations were rated as "strong recommendation", "recommendation" or "therapy option", based on Grading of Recommendations, Assessment, Development and Evaluation principles. In addition, evidence gaps were identified. RESULTS: The evidence resulted in 12 recommendations, 4 therapy options, and one statement for the prevention or treatment of PICS. RECOMMENDATIONS: early mobilization, motor training, and nutrition/dysphagia management should be performed. Delirium prophylaxis focuses on behavioral interventions. ICU diaries can prevent/treat psychological health issues like anxiety and post-traumatic stress disorders. Early rehabilitation approaches as well as long-term access to specialized rehabilitation centers are recommended. Therapy options include additional physical rehabilitation interventions. Statement: A prerequisite for the treatment of PICS are the regular and repeated assessments of the physical, cognitive and psychological health in patients at risk for or having PICS. CONCLUSIONS: PICS is a variable and complex syndrome that requires an individual multidisciplinary, and multiprofessional approach. Rehabilitation of PICS should include an assessment and therapy of motor-, cognitive-, and psychological health impairments.

Bilateral Arm Training vs Unilateral Arm Training for Severely Affected Patients With Stroke: Exploratory Single-Blinded Randomized Controlled Trial.

OBJECTIVE: To compare the effects of unilateral and bilateral arm training on arm impairment in severely affected patients with stroke. DESIGN: Single-blinded, randomized controlled trial. SETTING: Inpatient rehabilitation center. PARTICIPANTS: First-time subacute patients (N=69) with stroke and a nonfunctional hand. Patients were stratified according to lesion location post hoc. INTERVENTIONS: Repetitive bilateral arm training on an arm cycle followed by synchronized bilateral repetitive distal hand training or an identical unilateral arm training performed by the paretic limb only. Both unilateral and bilateral trainings were administered twice daily over 6 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was the Fugl-Meyer Assessment (FMA) score for the arm, and secondary measures were biomechanical parameters measuring isometric force and rate of force generation. Outcome measures were assessed before, at the end of, and 2 weeks after intervention. RESULTS: Patients were homogeneous at study onset. All patients improved regarding the FMA arm score and most biomechanical parameters after intervention. Yet the post hoc analysis stratifying patients according to lesion location showed that patients with pure subcortical stroke, but not patients with cortical involvement of stroke, showed a significantly greater improvement (P=.022) following the bilateral training in FMA arm score (from 6.8±5.7 to 17.8±15.8) compared with unilateral training (from 6.5±7.8 to 8.7±8.6). CONCLUSIONS: The benefit of bilateral arm training followed by repetitive bilateral hand training for motor control of the severely paretic upper limb may depend on lesion location. Further studies with larger sample size are required for the validation of these results.

Urine 4-(methylnitrosamino)-1-(3) pyridyl-1-butanol and cotinine in Alaska native postpartum women and neonates comparing smokers and smokeless tobacco users.

OBJECTIVE: Foetuses and neonates of women who use tobacco are exposed to nicotine and tobacco-derived carcinogens. We determined the relationship between urine biomarkers of tobacco toxicant exposure postpartum and in the neonates of Alaska Native (AN) women, comparing smokers and smokeless tobacco (ST) users, including iqmik, a homemade ST product. METHODS: AN women, including 36 smokers, 9 commercial ST and 16 iqmik users their neonates participated. Urine from the woman at the time of delivery and her neonate's first urine were analysed for cotinine, the major metabolite of nicotine, and 4-(methylnitrosamino)-1-(3) pyridyl-1-butanol (NNAL), a tobacco-specific carcinogen biomarker. RESULTS: Maternal urine cotinine and neonatal urine cotinine were strongly correlated in all tobacco use groups (r from 0.83 to 0.9, p < 0.002). Correlations between maternal cotinine and neonatal NNAL were moderately strong for cigarettes and commercial smokeless but weaker for iqmik users (r 0.73, 0.6 and 0.36, respectively). CONCLUSION: Correlations between maternal and neonatal biomarkers of tobacco toxicant exposure vary, dependent on tobacco product use. SIGNIFICANCE: This study provides novel data on biomarkers of tobacco exposure among postpartum AN women and their neonates. The results could be useful to guide future epidemiological studies of health risks associated with use of various tobacco products during pregnancy.

Exploratory Study of the Influence of Posture and Hand Task on Corticomotor Excitability of Upper Extremity Muscles After Stroke.

OBJECTIVE: To explore the interaction between postural stability and hand task on the corticospinal excitability (CE) of upper extremity muscles and how it is affected by lesion location. DESIGN: Cross-sectional explorative survey. SETTING: Inpatient rehabilitation center. PARTICIPANTS: Participants (N=81) were neurologically healthy subjects (volunteer sample, n=36) and patients with stroke (convenience sample, n=45; mean time since stroke, 45d), stratified according to lesion location: pure subcortical strokes (n=25) and strokes with cortical involvement (n=20). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Motor-evoked potentials were recorded simultaneously from the first dorsal interosseus (FDI) muscle and biceps brachii (BB) during rest and during low and forceful activation of the FDI in 4 different postural positions (supine, sitting, sitting unsupported, standing) and compared. RESULTS: Posture modulated CE of the FDI and BB during performance of a motor task but not at rest. The influence of postural position on CE of the FDI depended on force demand and lesion location: the control and subcortical stroke group demonstrated significantly higher CE of the FDI when performing the forceful task in the supine and stable sitting positions, respectively, compared with standing. In contrast, the cortical stroke group exhibited significantly higher CE of the FDI when performing the low-force task in a stable sitting position compared with standing. CONCLUSIONS: Posture influences CE of the FDI and BB in healthy subjects and patients with stroke differentially depending on hand task, but not at rest. A stable sitting posture increased excitability of the FDI in patients with stroke. These findings imply that hand rehabilitation protocols may be influenced by posture.

Fetal Exposure to Carcinogens With Tobacco Use in Pregnancy: Phase 1 MAW Study Findings.

INTRODUCTION: The high prevalence of smoking and smokeless tobacco (ST) use during pregnancy in Alaska Native (AN) women is concerning due to the detrimental effects of these products to the mother and the developing fetus. We sought to correlate maternal cotinine levels with fetal exposure to a tobacco-specific carcinogen to incorporate in a biomarker feedback intervention to motivate tobacco cessation during pregnancy. METHODS: Demographic and tobacco use data were collected from a convenience sample of pregnant AN smokers, ST users, and non-users. Maternal and neonatal urine were collected at delivery. Maternal urine cotinine and neonatal urine total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, a tobacco-specific carcinogen) levels in smokers and ST users were analyzed and their correlations determined by Spearman correlation coefficients. RESULTS: During 2012-2014, we enrolled 64 non-users, 54 smokers, and 30 ST (20 homemade iqmik; 10 commercial ST) users (n = 148). Analyses of paired maternal-infant urine samples obtained for 36 smokers demonstrated a moderate to strong correlation (r = 0.73, P < .001) between maternal cotinine and infant NNAL levels. The correlation was not significant for 25 iqmik users (r = 0.36, P = .17) or 9 commercial ST users (r = 0.60, P = .09). No analysis was conducted for 55 non-users with cotinine and NNAL levels < limits of quantification. CONCLUSIONS: There is a moderate to strong correlation between maternal smoking and fetal exposure to the tobacco-specific carcinogen NNAL. IMPLICATIONS: The correlation between maternal smoking and fetal carcinogen exposure may provide an education tool to help motivate smoking cessation among pregnant AN women. Further investigation is warranted to determine correlations between maternal commercial ST and iqmik use and neonatal NNAL.

Neuroendocrine Disturbances One to Five or More Years after Traumatic Brain Injury and Aneurysmal Subarachnoid Hemorrhage: Data from the German Database on Hypopituitarism.

Neuroendocrine disturbances are common after traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH), but only a few data exist on long-term anterior pituitary deficiencies after brain injury. We present data from the Structured Data Assessment of Hypopituitarism after TBI and SAH, a multi-center study including 1242 patients. We studied a subgroup of 351 patients, who had sustained a TBI (245) or SAH (106) at least 1 year before endocrine assessment (range 1-55 years) in a separate analysis. The highest prevalence of neuroendocrine disorders was observed 1-2 years post-injury, and it decreased over time only to show another maximum in the long-term phase in patients with brain injury occurring ≥5 years prior to assessment. Gonadotropic and somatotropic insufficiencies were most common. In the subgroup from 1 to 2 years after brain injury (n = 126), gonadotropic insufficiency was the most common hormonal disturbance (19%, 12/63 men) followed by somatotropic insufficiency (11.5%, 7/61), corticotropic insufficiency (9.2%, 11/119), and thyrotropic insufficiency (3.3%, 4/122). In patients observed ≥ 5 years after brain injury, the prevalence of somatotropic insufficiency increased over time to 24.1%, whereas corticotropic and thyrotrophic insufficiency became less frequent (2.5% and 0%, respectively). The prevalence differed regarding the diagnostic criteria (laboratory values vs. physician`s diagnosis vs. stimulation tests). Our data showed that neuroendocrine disturbances are frequent even years after TBI or SAH, in a cohort of patients who are still on medical treatment.

Group therapy task training versus individual task training during inpatient stroke rehabilitation: a randomised controlled trial.

OBJECTIVE: To compare the efficacy of intensive daily applied progressive group therapy task training with equally dosed individual progressive task training on self-reported mobility for patients with moderate to severe stroke during inpatient rehabilitation. DESIGN: Randomized controlled clinical trial. SETTING: In-patient rehabilitation center. SUBJECTS: A total of 73 subacute patients with stroke who were not able to walk without physical assistance at randomisation. INTERVENTIONS: Patients were allocated to group therapy task training (GT) or individual task training (IT). Both interventions were intended to improve walking competency and comprised 30 sessions of 90 minutes over six weeks. MAIN MEASURES: Primary outcome was the mobility domain of the Stroke Impact Scale (SIS-3.0). Secondary outcomes were the other domains of SIS-3.0, standing balance, gait speed, walking distance, stair climbing, fatigue, anxiety and depression. RESULTS: No adverse events were reported in either arm of the trial. There were no significant differences between groups for the SIS mobility domain at the end of the intervention (Z= -0.26, P = 0.79). No significant differences between groups were found in gait speed improvements (GT:0.38 ±0.23; IT:0.26±0.35), any other gait related parameters, or in non-physical outcomes such as depression and fatigue. CONCLUSION: Inpatient group therapy task training for patients with moderate to severe stroke is safe and equally effective as a dose-matched individual task training therapy. Group therapy task training may be delivered as an alternative to individual therapy or as valuable adjunct to increase time spent in gait-related activities.

Interrelation between Neuroendocrine Disturbances and Medical Complications Encountered during Rehabilitation after TBI.

Traumatic brain injury is not a discrete event but an unfolding sequence of damage to the central nervous system. Not only the acute phase but also the subacute and chronic period after injury, i.e., during inpatient rehabilitation, is characterized by multiple neurotransmitter alterations, cellular dysfunction, and medical complications causing additional secondary injury. Neuroendocrine disturbances also influence neurological outcome and are easily overlooked as they often present with diffuse symptoms such as fatigue, depression, poor concentration, or a decline in overall cognitive function; these are also typical sequelae of traumatic brain injury. Furthermore, neurological complications such as hydrocephalus, epilepsy, fatigue, disorders of consciousness, paroxysmal sympathetic hyperactivity, or psychiatric-behavioural symptoms may mask and/or complicate the diagnosis of neuroendocrine disturbances, delay appropriate treatment and impede neurorehabilitation. The present review seeks to examine the interrelation between neuroendocrine disturbances with neurological complications frequently encountered after moderate to severe TBI during rehabilitation. Common neuroendocrine disturbances and medical complications and their clinical implications are discussed.

Genetic and phenotypic variation in UGT2B17, a testosterone-metabolizing enzyme, is associated with BMI in males.

OBJECTIVE: A number of candidate gene and genome-wide association studies have identified significant associations between single nucleotide polymorphisms, particularly in FTO and MC4R, and body weight. However, the association between copy number variation and body weight is less understood. Anabolic androgenic steroids, such as testosterone, can regulate body weight. In humans, UDP-glucuronosyltransferase 2B17 (UGT2B17) metabolizes testosterone to a metabolite, which is readily excreted in urine. We investigate the association between genetic and phenotypic variation in UGT2B17 and body weight. MATERIALS AND METHODS: UGT2B17 deletion was genotyped and in-vivo UGT2B17 enzymatic activity (as measured by the 3-hydroxycotinine glucuronide to free 3-hydroxycotinine ratio) was measured in 400 Alaska Native individuals and 540 African Americans. RESULTS: In Alaska Native people, UGT2B17 deletion was strongly associated with lower BMI in male individuals (P<0.001), but not in female individuals, consistent with testosterone being a male dominant steroid. The sex-specific association between UGT2B17 deletion and lower BMI was also observed in African Americans (P=0.01 in male individuals). In both populations, UGT2B17 deletion was significantly associated with lower measured in-vivo UGT2B17 activity. In male individuals, lower in-vivo UGT2B17 activity was associated with lower BMI, as observed in the sex-specific genotypic association. CONCLUSION: These data suggest that UGT2B17 deletion leads to reduced UGT2B17 activity, and lower BMI in male individuals. This is consistent with the hypothesis that reduced UGT2B17-mediated testosterone excretion results in higher testosterone levels. Future studies could confirm this hypothesis by directly measuring serum testosterone levels.

CHRNA5-A3-B4 genetic variants alter nicotine intake and interact with tobacco use to influence body weight in Alaska Native tobacco users.

BACKGROUND AND AIMS: Gene variants in CHRNA5-A3-B4, which encode for the α5, α3 and ß4 nicotinic receptor subunits, are associated with altered smoking behaviors in European Americans. Little is known about CHRNA5-A3-B4 and its association with smoking behaviors and weight in Alaska Native people, which is a population with high prevalence but low levels of tobacco consumption, extensive smokeless tobacco use and high rates of obesity. We investigated CHRNA5-A3-B4 haplotype structure and its association with nicotine intake and obesity in Alaska Native people. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional study of 400 Alaska Native individuals, including 290 tobacco users. MEASUREMENTS: CHRNA5-A3-B4 genotype, body weight and tobacco consumption biomarkers such as plasma cotinine and urinary total nicotine equivalents (TNE). FINDINGS: Alaska Native people have a distinct CHRNA5-A3-B4 haplotype structure compared with European/African Americans. In 290 Alaska Native tobacco users the 'G' allele of rs578776, which tagged a 30 kb haplotype in CHRNA5-A3-B4, was prevalent (16%) and associated significantly with nicotine intake (20% higher plasma cotinine, P < 0.001, 16% higher TNE, P = 0.076), while rs16969968 was not associated with nicotine intake. Rs578776 acted in combination with CYP2A6, the main nicotine-metabolizing enzyme, to increase nicotine intake by 1.8-fold compared with the low-risk group (P < 0.001). Furthermore, rs2869950, a single nucleotide polymorphism 5' to CHRNB4, was associated significantly with increased body mass index (P < 0.01) in the tobacco users even after controlling for differences in nicotine intake (P < 0.01). CONCLUSIONS: Genetic variants in CHRNA5-A3-B4 alter nicotine intake and body mass index in a population of Alaska Native people, who have a distinct haplotype structure, smoking behaviors and prevalence of obesity.

The ability of plasma cotinine to predict nicotine and carcinogen exposure is altered by differences in CYP2A6: the influence of genetics, race, and sex.

BACKGROUND: Cotinine, a nicotine metabolite, is a biomarker of tobacco, nicotine, and carcinogen exposure. However, a given cotinine level may not represent the same tobacco exposure; for example, African-Americans have higher cotinine levels than Caucasians after controlling for exposure. METHODS: Cotinine levels are determined by the amount of cotinine formation and the rate of cotinine removal, which are both mediated by the enzyme CYP2A6. Because CYP2A6 activity differs by sex (estrogen induces CYP2A6) and genotype, their effect on cotinine formation and removal was measured in nonsmoking Caucasians (Study 1, n = 181) infused with labeled nicotine and cotinine. The findings were then extended to ad libitum smokers (Study 2, n = 163). RESULTS: Study 1: Reduced CYP2A6 activity altered cotinine formation less than cotinine removal resulting in ratios of formation to removal of 1.31 and 1.12 in CYP2A6 reduced and normal metabolizers (P = 0.01), or 1.39 and 1.12 in males and females (P = 0.001), suggesting an overestimation of tobacco exposure in slower metabolizers. Study 2: Cotinine again overestimated tobacco and carcinogen exposure by 25% or more in CYP2A6 reduced metabolizers (≈2-fold between some genotypes) and in males. CONCLUSIONS: In people with slower relative to faster CYP2A6 activity, cotinine accumulates resulting in substantial differences in cotinine levels for a given tobacco exposure. IMPACT: Cotinine levels may be misleading when comparing those with differing CYP2A6 genotypes within a race, between races with differing frequencies of CYP2A6 gene variants (i.e., African-Americans have higher frequencies of reduced function variants contributing to their higher cotinine levels), or between the sexes.

Chemical analysis of Alaskan Iq'mik smokeless tobacco.

INTRODUCTION: Iq'mik, a form of smokeless tobacco (ST), is traditionally used by Cup'ik and Yup'ik Eskimo people of western Alaska. Iq'mik is sometimes incorrectly considered to be a healthier alternative to smoking because its ingredients are perceived as "natural." Our chemical characterization of iq'mik shows that iq'mik is not a safe alternative to smoking or other ST use. METHODS: We measured nicotine and pH levels of tobacco and ash used to prepare iq'mik. We also characterized levels of toxins which are known to be present in ST including tobacco-specific nitrosamines (TSNAs) and polycyclic aromatic hydrocarbons (PAHs) using chromatographic separations coupled with isotope dilution mass spectrometry. RESULTS: Nicotine content in the iq'mik tobacco was very high, ranging from 35 to 43 mg/g, with a mean of 39 mg/g. The pH of the iq'mik tobacco-ash mixture was 11, an extremely high level compared with most ST products. High levels of PAHs were seen in the fire-cured tobacco samples with a benzo[a]pyrene level of 87 ng/g. Average TSNA levels in the tobacco were 34, 2,700, and 340 ng/g for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), N'-nitrosonornicotine (NNN), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), respectively. CONCLUSIONS: Iq'mik contains high levels of the more easily absorbed unionized nicotine as well as known carcinogenic TSNAs and PAHs. The perception that iq'mik is less hazardous than other tobacco products due to the use of "natural" ingredients is not warranted. This chemical characterization of iq'mik gives a better understanding of the risk of possible adverse health effects of its use.

Tobacco use among southwestern Alaska Native people.

INTRODUCTION: We examined the characteristics, attitudes, beliefs, and exposure to tobacco products in a cohort of rural dwelling Alaska Native (AN) people. METHODS: We conducted a study of 400 of AN adult tobacco users and nonusers living in Southwestern Alaska. Questionnaires covered variables such as demographics, tobacco-use history, current tobacco use and dependence scales, general health status, attitudes and beliefs about tobacco, and quitting history. RESULTS: The study population smoked 7.8 cigarettes per day compared with 16.8 on average for the U.S. population: a significant proportion of the population engaged in dual use of cigarettes and smokeless tobacco products. Over one third (40.9%), first tried tobacco at age 11 or younger. The mean measures of tobacco addiction (e.g., Fagerstrom Test for Nicotine Dependence, Severson Scale of Smokeless Tobacco Dependence) scores were lower compared with other U.S. populations. CONCLUSIONS: Very high tobacco-use prevalence, dual product use, and early tobacco use are observed in Southwestern AN people. Unexpectedly these did not appear to be correlated with heavier individual tobacco use or higher levels of addiction in this population.

Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco-specific nitrosamine exposure and lower tobacco-specific nitrosamine bioactivation.

Nicotine, the psychoactive ingredient in tobacco, is metabolically inactivated by CYP2A6 to cotinine. CYP2A6 also activates procarcinogenic tobacco-specific nitrosamines (TSNA). Genetic variation in CYP2A6 is known to alter smoking quantity and lung cancer risk in heavy smokers. Our objective was to investigate how CYP2A6 activity influences tobacco consumption and procarcinogen levels in light smokers and smokeless tobacco users. Cigarette smokers (n = 141), commercial smokeless tobacco users (n = 73) and iqmik users (n = 20) were recruited in a cross-sectional study of Alaska Native people. The participants' CYP2A6 activity was measured by both endophenotype and genotype, and their tobacco and procarcinogen exposure biomarker levels were also measured. Smokers, smokeless tobacco users and iqmik users with lower CYP2A6 activity had lower urinary total nicotine equivalents (TNE) and (methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL) levels (a biomarker of TSNA exposure). Levels of N-nitrosonornicotine (NNN), a TSNA metabolically bioactivated by CYP2A6, were higher in smokers with lower CYP2A6 activities. Light smokers and smokeless tobacco users with lower CYP2A6 activity reduce their tobacco consumption in ways (e.g. inhaling less deeply) that are not reflected by self-report indicators. Tobacco users with lower CYP2A6 activity are exposed to lower procarcinogen levels (lower NNAL levels) and have lower procarcinogen bioactivation (as indicated by the higher urinary NNN levels suggesting reduced clearance), which is consistent with a lower risk of developing smoking-related cancers. This study demonstrates the importance of CYP2A6 in the regulation of tobacco consumption behaviors, procarcinogen exposure and metabolism in both light smokers and smokeless tobacco users.

The influence of gender on the injury severity, course and outcome of traumatic brain injury.

OBJECTIVE: To examine the independent association of gender with injury severity, clinical course, pituitary dysfunction and outcome after traumatic brain injury (TBI). DESIGN: Prospective cohort, analysis of a data sub-set collected as part of the nation-wide database 'The Structured Data Assessment of Hypopituitarism after TBI and SAH'. METHODS AND PROCEDURES: Four hundred and twenty-seven patients following TBI were observed from acute care through neurological rehabilitation. Outcome was measured by Glasgow Outcome Scale (GOS), employment status and living situation post-injury. As a secondary outcome measure anterior pituitary function was assessed. RESULTS: There were no differences in injury severity between men and women. Age had a significant effect on the GCS score (p = 0.0295), but gender did not (p = 0.4105). The outcome was equivalent between men and women once corrected for age. Logistic regression revealed that gender had no effect (p = 0.8008), but age (p = 0.0021) and initial injury severity (p = 0.0010) had an effect on the GOS. After correcting for pre-injury living situation and employment only initial injury severity (p = 0.0005) influenced GOS. Pituitary insufficiency was not affected by sex or age. CONCLUSION: Gender does not seem to influence the course and outcome of TBI. Outcome parameters were affected foremost by initial injury severity and by age, but not by sex.

CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people.

OBJECTIVES: Alaska Native (AN) people have a high prevalence of tobacco use and associated morbidity and mortality when compared with the general USA population. Variations in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, have not been characterized in AN and may contribute toward the increased risk. METHODS: AN people (n=400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use. They were genotyped for CYP2A6*1X2A, *1X2B, *1B, *2, *4, *7, *8, *9, *10, *12, *17, *35 and CYP2B6*4, *6, *9 and provided plasma and urine samples for the measurement of nicotine and metabolites. RESULTS: CYP2A6 and CYP2B6 variant frequencies among the AN Yupik people (n=361) were significantly different from those in other ethnicities. Nicotine metabolism [as measured by the plasma and urinary ratio of metabolites trans-3'-hydroxycotinine to cotinine (3HC/COT)] was significantly associated with CYP2A6 (P<0.001), but not CYP2B6 genotype (P=0.95) when controlling for known covariates. It was noteworthy that the plasma 3HC/COT ratios were high in the entire Yupik people, and among the Yupik CYP2A6 wild-type participants, they were substantially higher than those in previously characterized racial/ethnic groups (P<0.001 vs. Caucasians and African Americans). CONCLUSION: Yupik AN people have a unique CYP2A6 genetic profile that associated strongly with in-vivo nicotine metabolism. More rapid CYP2A6-mediated nicotine and nitrosamine metabolism in the Yupik people may modulate the risk of tobacco-related diseases.

Exposure to nicotine and carcinogens among Southwestern Alaskan Native cigarette smokers and smokeless tobacco users.

BACKGROUND: The prevalence of tobacco use, both cigarette smoking and smokeless, including iqmik (homemade smokeless tobacco prepared with dried tobacco leaves mixed with alkaline ash), and of tobacco-related cancer is high in Alaskan Native people (AN). To investigate possible mechanisms of increased cancer risk we studied levels of nicotine and tobacco-specific nitrosamines (TSNA) in tobacco products and biomarkers of tobacco toxicant exposure in Southwestern AN people. METHODS: Participants included 163 cigarette smokers, 76 commercial smokeless tobacco, 20 iqmik, 31 dual cigarette smokers and smokeless tobacco, and 110 nontobacco users. Tobacco use history, samples of tobacco products used, and blood and urine samples were collected. RESULTS: Nicotine concentrations were highest in cigarette tobacco and TSNAs highest in commercial smokeless tobacco products. The AN participants smoked on average 7.8 cigarettes per day. Nicotine exposure, assessed by several biomarker measures, was highest in iqmik users, and similar in smokeless tobacco and cigarette smokers. TSNA exposure was highest in smokeless tobacco users, and polycyclic aromatic hydrocarbon exposure was highest in cigarette smokers. CONCLUSIONS: Despite smoking fewer cigarettes per day, AN cigarette smokers had similar daily intake of nicotine compared to the general U.S. population. Nicotine exposure was greatest from iqmik, likely related to its high pH due to preparation with ash, suggesting high addiction potential compared to other smokeless tobacco products. TSNA exposure was much higher with smokeless tobacco than other product use, possibly contributing to the high rates of oral cancer. IMPACT: Our data contribute to an understanding of the high addiction risk of iqmik use and of the cancer-causing potential of various forms of tobacco use among AN people.

Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: the German interdisciplinary database.

Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5±19.7 years; 417 SAH, age 49.7±11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests.