Tobacco and ADHD: A Role of MAO-Inhibition in Nicotine Dependence and Alleviation of ADHD Symptoms.

Attention-deficit/hyperactivity disorder (ADHD) is a relatively commonly occurring neurodevelopmental disorder affecting approximately 5% of children and young people. The neurobiological mechanisms of ADHD are proposed to particularly center around increased dopamine receptor availability related to associated symptoms of reduced attention regulation and impulsivity. ADHD is also persistent across the lifespan and associated with a raft of impulsive and health-risk behaviors including substance abuse and smoking. Research highlighting the potentially significant levels of monoamine oxidase (MAO) inhibitory properties in tobacco smoke and e-cigarettes may provide a mechanism for increased tobacco smoke dependence among those with ADHD, in addition to the role of nicotine. Aim: This scoping review aimed to establish evidence for the above neurobiological pathway between smoking and ADHD symptom-alleviation or "self-medication" with the inclusion of the mechanism of MAO-inhibitors indirect increasing dopamine in the brain. Methodology: Scoping review methodologies were employed in this review selected to synthesize multiple sources of empirical research to identify current gaps in the knowledge base and identify key characteristics of research data related to a phenomenon. Databases searched included OVID MEDLINE(R), Embase, Cochrane, PsycINFO and SCOPUS limited to 2000 onward and empirically validated, peer-reviewed research. Findings: There is support for the role of MAO-inhibition on greater reinforcement of smoking for individuals with ADHD through a greater impact on dopaminergic availability than nicotine; potentially moderating ADHD symptoms. Conclusion: Greater support for a "self-medication" model of ADHD and smoking includes not only nicotine but also MAO-inhibitors as dopamine agonists contained in cigarettes and e-cigarettes.

Hypertension and diabetes management: a policy perspective from Ghana.

PURPOSE: The purpose of this paper is to assess policy and management of hypertension and diabetes in Ghana. DESIGN/METHODOLOGY/APPROACH: The authors conducted 26 key informant interviews with policy makers, payers, providers and participants from advocacy groups associated with the management of hypertension and diabetes both at national and district levels in Ghana; conducted focus group discussions with a total of 18 hypertensive and diabetic patients; and analyzed documentation detailing activities that have been undertaken in response to the management of hypertension and diabetes in Ghana. The authors then conducted a content analysis after combining the three sources of information. FINDINGS: Using a stepwise policy process, the Ghanaian health sector has developed overarching policies and strategies on management of diabetes, hypertension, other non-communicable diseases, tobacco, alcohol and nutrition-related issues. Availability of funds and over-concentration on communicable diseases are the main barriers to the implementation of policies. Besides, response of the health sector to address the problems of hypertension and diabetes is focused more on clinical management than prevention; while the structures and processes to manage diabetes and hypertension is available at all levels of service delivery, more needs to be done on preventive aspects. ORIGINALITY/VALUE: This is the first study in Ghana to combine individual interviews, focus groups and document analysis to review policy development, implementation and response activities on the management of hypertension and diabetes. The authors believe that the evidence from this research will inform future policy initiatives on hypertension and diabetes management in Ghana.

Transcription factor YY1 can control AID-mediated mutagenesis in mice.

Activation-induced cytidine deminase (AID) is crucial for controlling the immunoglobulin (Ig) diversification processes of somatic hypermutation (SHM) and class switch recombination (CSR). AID initiates these processes by deamination of cytosine, ultimately resulting in mutations or double strand DNA breaks needed for SHM and CSR. Levels of AID control mutation rates, and off-target non-Ig gene mutations can contribute to lymphomagenesis. Therefore, factors that control AID levels in the nucleus can regulate SHM and CSR, and may contribute to disease. We previously showed that transcription factor YY1 can regulate the level of AID in the nucleus and Ig CSR. Therefore, we hypothesized that conditional knock-out of YY1 would lead to reduction in AID localization at the Ig locus, and reduced AID-mediated mutations. Using mice that overexpress AID (IgκAID yy1f/f ) or that express normal AID levels (yy1f/f ), we found that conditional knock-out of YY1 results in reduced AID nuclear levels, reduced localization of AID to the Sµ switch region, and reduced AID-mediated mutations. We find that the mechanism of YY1 control of AID nuclear accumulation is likely due to YY1-AID physical interaction which blocks AID ubiquitination.

Chronic Paraspinal Pain due to Multiple Aortic Aneurysms.

Aneurysms of the aorta are not uncommon, both of the thoracic aorta or the abdominal aorta and may be associated with congenital aortic valve diseases, cystic medial necrosis, Marfan's Syndrome or Ehlers-Danlos syndrome, or atherosclerosis. We report a case of a 46 year old smoker who had developed multiple aneurysms of the aorta in both the thoracic and abdominal parts and was incidentally diagnosed on work-up of a chronic back pain associated with venous prominence on left side of chest and left arm.

YY1 controls Igκ repertoire and B-cell development, and localizes with condensin on the Igκ locus.

Conditional knock-out (KO) of Polycomb Group (PcG) protein YY1 results in pro-B cell arrest and reduced immunoglobulin locus contraction needed for distal variable gene rearrangement. The mechanisms that control these crucial functions are unknown. We deleted the 25 amino-acid YY1 REPO domain necessary for YY1 PcG function, and used this mutant (YY1ΔREPO), to transduce bone marrow from YY1 conditional KO mice. While wild-type YY1 rescued B-cell development, YY1ΔREPO failed to rescue the B-cell lineage yielding reduced numbers of B lineage cells. Although the IgH rearrangement pattern was normal, there was a selective impact at the Igκ locus that showed a dramatic skewing of the expressed Igκ repertoire. We found that the REPO domain interacts with proteins from the condensin and cohesin complexes, and that YY1, EZH2 and condensin proteins co-localize at numerous sites across the Ig kappa locus. Knock-down of a condensin subunit protein or YY1 reduced rearrangement of Igκ Vκ genes suggesting a direct role for YY1-condensin complexes in Igκ locus structure and rearrangement.

Small-signal neural models and their applications.

This paper introduces the use of the concept of small-signal analysis, commonly used in circuit design, for understanding neural models. We show that neural models, varying in complexity from Hodgkin-Huxley to integrate and fire have similar small-signal models when their corresponding differential equations are close to the same bifurcation with respect to input current. Three applications of small-signal neural models are shown. First, some of the properties of cortical neurons described by Izhikevich are explained intuitively through small-signal analysis. Second, we use small-signal models for deriving parameters for a simple neural model (such as resonate and fire) from a more complicated but biophysically relevant one like Morris-Lecar. We show similarity in the subthreshold behavior of the simple and complicated model when they are close to a Hopf bifurcation and a saddle-node bifurcation. Hence, this is useful to correctly tune simple neural models for large-scale cortical simulations. Finaly, the biasing regime of a silicon ion channel is derived by comparing its small-signal model with a Hodgkin-Huxley-type model.

Mechanisms of Yin Yang 1 in oncogenesis: the importance of indirect effects.

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that performs numerous functions including transcriptional regulation, cell growth control, apoptosis, large-scale chromosomal dynamics, and X-chromosome inactivation. YY1 clearly is able to control cell functions, including proliferation, by acting as a transcription factor either to activate or repress specific genes. Based on its ability to regulate cell growth control genes, it has been argued that YY1 can function as an oncogene that initiates oncogenesis. Although this is an attractive hypothesis, no reports indicate that YY1 can acutely transform cells in culture or form tumors within animals when overexpressed. Thus, it remains unclear whether YY1 is a "classic" oncogene. However, YY1 controls many diverse cell functions, and these functions may provide clues to its role in oncogenesis. We propose that in many cases YY1 may function in oncogenesis and disease progression through "indirect" effects by virtue of its role in either recruiting Polycomb group proteins to DNA, regulating mutator protein accumulation, controlling large-scale chromosomal dynamics or genomic integrity. Disruption of these functions may causally initiate cancer or may contribute to disease progression. Targeting YY1 functions provides possible avenues for clinical intervention.

Dynamics and bifurcations in a silicon neuron.

In this paper, the nonlinear dynamical phenomenon associated with a silicon neuron are described. The neuron has one transient sodium (activating and inactivating) channel and one activating potassium channel. These channels do not model specific equations; instead they directly mimic the desired voltage clamp responses. This allows us to create silicon structures that are very compact (six transistors and three capacitors) with activation and inactivation parameters being tuned by floating-gate (FG) transistors. Analysis of the bifurcation conditions allow us to identify regimes in the parameter space that are desirable for biasing the circuit. We show a subcritical Hopf-bifurcation which is characteristic of class 2 excitability in Hodgkin-Huxley (H-H) neurons. We also show a Hopf bifurcation at higher values of stimulating current, a phenomenon also observed in real neurons and termed excitation block. The phenomenon of post-inhibitory rebound and frequency preference are displayed and intuitive explanations based on the circuit are provided. The compactness and low-power nature of the circuit shall allow us to integrate a large number of these neurons on a chip to study complicated network behavior.

Evaluation of cell types for assessment of cytogenetic damage in arsenic exposed population.

BACKGROUND: Cytogenetic biomarkers are essential for assessing environmental exposure, and reflect adverse human health effects such as cellular damage. Arsenic is a potential clastogen and aneugen. In general, the majority of the studies on clastogenic effects of arsenic are based on frequency of micronuclei (MN) study in peripheral lymphocytes, urothelial and oral epithelial cells. To find out the most suitable cell type, here, we compared cytogenetic damage through MN assay in (a) various populations exposed to arsenic through drinking water retrieved from literature review, as also (b) arsenic-induced Bowen's patients from our own survey. RESULTS: For literature review, we have searched the Pubmed database for English language journal articles using the following keywords: "arsenic", "micronuclei", "drinking water", and "human" in various combinations. We have selected 13 studies consistent with our inclusion criteria that measured micronuclei in either one or more of the above-mentioned three cell types, in human samples. Compared to urothelial and buccal mucosa cells, the median effect sizes measured by the difference between people with exposed and unexposed, lymphocyte based MN counts were found to be stronger. This general pattern pooled from 10 studies was consistent with our own set of three earlier studies. MN counts were also found to be stronger for lymphocytes even in arsenic-induced Bowen's patients (cases) compared to control individuals having arsenic-induced non-cancerous skin lesions. CONCLUSION: Overall, it can be concluded that MN in lymphocytes may be superior to other epithelial cells for studying arsenic-induced cytogenetic damage.

Increased chromosome aberration frequencies in the Bowen's patients compared to non-cancerous skin lesions individuals exposed to arsenic.

Cytogenetic biomarkers are essential for assessing environmental exposure that can predict adverse human health effects such as cellular damage. Chromosomal aberrations are the most important cytogenetic end-points successfully used for the cancer risk assessment of populations occupationally or environmentally exposed to different toxic chemicals. Previous reports suggest that, increased frequency of chromosomal aberration (CA), in peripheral blood lymphocytes, is a predictor of cancer. Arsenic is a paradoxical human carcinogen, clastogen and aneugen. Despite of exposure at similar extent, only 15-20% of individuals show arsenic induced skin lesions including Bowen's disease (BD). Previously we have reported the significant increase in CA in the individuals with arsenic induced skin lesions when compared to individuals without any skin lesions, drinking arsenic contaminated water at similar extent. Presently, a matched case-control study was performed to examine whether biomarkers such as chromosomal aberrations can predict the development of arsenic induced Bowen's (in situ carcinoma) diseases. Chromosomal aberrations (both chromosome and chromatid types) and mitotic index were analyzed from the lymphocytes of 25 cases of Bowen's patient which was compared to matched control from the individuals with arsenic induced non-cancerous skin lesions such as raindrop pigmentation, keratosis of palm and sole, hypo and hyper pigmentation. Chromosomal aberrations/cell, chromosome type aberrations and total percentage of aberrant cells were significantly higher in cases compared to control (p<0.01). These results suggest that chromosomal aberrations can be used for cancer risk assessment of the population exposed to arsenic through drinking water.

Comparison of health effects between individuals with and without skin lesions in the population exposed to arsenic through drinking water in West Bengal, India.

A study was conducted to explore the effect of arsenic causing conjunctivitis, neuropathy and respiratory illness in individuals, with or without skin lesions, as a result of exposure through drinking water, contaminated with arsenic to similar extent. Exposed study population belongs to the districts of North 24 Parganas and Nadia, West Bengal, India. A total of 725 exposed (373 with skin lesions and 352 without skin lesions) and 389 unexposed individuals were recruited as study participants. Participants were clinically examined and interviewed. Arsenic content in drinking water, urine, nail and hair was estimated. Individuals with skin lesion showed significant retention of arsenic in nail and hair and lower amount of urinary arsenic compared to the group without any skin lesion. Individuals with skin lesion also showed higher risk for conjunctivitis ((odd's ratio) OR: 7.33, 95% CI: 5.05-10.59), peripheral neuropathy (OR: 3.95, 95% CI: 2.61-5.93) and respiratory illness (OR: 4.86, 95% CI: 3.16-7.48) compared to the group without any skin lesion. The trend test for OR of the three diseases in three groups was found to be statistically significant. Again, individuals without skin lesion in the exposed group showed higher risk for conjunctivitis (OR: 4.66, 95% CI: 2.45-8.85), neuropathy (OR: 3.99, 95% CI: 1.95-8.09), and respiratory illness (OR: 3.21, 95% CI: 1.65-6.26) when compared to arsenic unexposed individuals. Although individuals with skin lesions were more susceptible to arsenic-induced toxicity, individuals without skin lesions were also subclinically affected and are also susceptible to arsenic-induced toxicity and carcinogenicity when compared to individuals not exposed to arsenic.

Blood concentrations of methionine, selenium, beta-carotene, and other micronutrients in a case-control study of arsenic-induced skin lesions in West Bengal, India.

Previous studies have suggested that susceptibility to arsenic toxicity could be influenced by micronutrients, in particular selenium, methionine, and beta-carotene. A case-control study was conducted in West Bengal, India, in a region known to have groundwater arsenic contamination, to determine whether differences in micronutrient status contribute to susceptibility to arsenic-induced skin lesions. Micronutrient status was assessed by blood levels of specific micronutrients and metabolic indicators. Blood was obtained from 180 cases with skin lesions and 192 controls. Blood assays measured micronutrients and carotenoids (folate, selenium, vitamin B12, vitamin B6, retinol, alpha-tocopherol, lutein/zeaxanthin, beta-carotene, lycopene, beta-cryptoxanthin) and metabolic indicators such as glucose, cholesterol, transthyretin, amino acids, and proteins potentially associated with methylation (cysteine, homocysteine, methionine, glutathione). The distributions of nutrient concentrations were similar in cases and controls. The median selenium concentrations in cases and controls were both 1.15 micromol/L, and there was little evidence of differences in other micronutrients. Odds ratios (ORs) for arsenic-induced skin lesions were estimated for each quartile of nutrient concentrations, using the quartile with the highest nutrient level as the referent group. There were no clear trends associated with deficiencies of any micronutrient or metabolic indicator. For decreasing quartiles of selenium, the OR estimates were 1.00, 0.67, 0.99, 0.80; P=0.81; for methionine, the OR estimates were 1.00, 0.83, 0.78, 0.72; P=0.29. For beta-carotene, the ORs were 1.00, 0.53, 0.51, 0.96, demonstrating no increased risk at the lower quartiles. The measured micronutrients and metabolic indicators investigated do not appear to modify the risk of developing arsenic-induced skin lesions. The lack of any trend of increasing risk with lower selenium, vitamin E, and beta-carotene concentrations has important implications for proposed therapeutic interventions. The emphasis of interventions should be on reducing arsenic exposure.

Study of urban community survey in India: growing trend of high prevalence of hypertension in a developing country.

The prevalence pattern of hypertension in developing countries is different from that in the developed countries. In India, a very large, populous and typical developing country, community surveys have documented that between three and six decades, prevalence of hypertension has increased by about 30 times among urban dwellers and by about 10 times among the rural inhabitants. Various factors might have contributed to this rising trend and among others, consequences of urbanization such as change in life style pattern, diet and stress, increased population and shrinking employment have been implicated. In this paper, we study the prevalence of hypertension in an urban community of India using the JNC VII criteria, with the aim of identifying the risk factors and suggesting intervention strategies. A total of 1609 respondents out of 1662 individuals participated in our cross-sectional survey of validated and structured questionnaire followed by blood pressure measurement. Results showed pre-hypertensive levels of blood pressures among 35.8% of the participants in systolic group (120-139mm of Hg) and 47.7% in diastolic group (80-89 mm of Hg). Systolic hypertension (140 mm of Hg) was present in 40.9% and diastolic hypertension (90 mm of Hg) in 29.3% of the participants. Age and sex-specific prevalence of hypertension showed progressive rise of systolic and diastolic hypertension in women when compared to men. Men showed progressive rise in systolic hypertension beyond fifth decade of life. Bivariate analysis showed significant relationship of hypertension with age, sedentary occupation, body mass index (BMI), diet, ischemic heart disease, and smoking. Multivariate analysis revealed age and BMI as risk factors, and non-vegetarian diet as protective factor with respect to hypertension. Prevalence of prehypertensives was high among younger subjects - particularly students and laborers who need special attention. Role of non-vegetarian diet as a protective factor might have been related to fish-eating behavior of the sample population, who also use mustard oil as cooking medium - both of which have significant level of essential polyunsaturated fatty acids. The observed prevalence of hypertension in this study and other studies suggest the need for a comprehensive national policy to control hypertension in India, and, in other similar developing countries.

A 5 years prospective study of incidence, morbidity and mortality profile of stroke in a rural community of eastern India.

Community-based longitudinal study on stroke is rare in India. It has been predicted that the stroke incidence will be higher in developing countries than developed countries. Hence a five years prospective study was planned to carry out in the rural Bengal, India based on WHO protocol to determine the incidence rate, risk factors, morbidity and mortality profile of stroke. In a two-stage procedure, 20717 subjects out of 20842 people from a cluster of 12 villages was surveyed by house-to-house method and the screened cases were examined by a team of neurologists including post stroke surveillance for one year. Altogether 128 first ever stroke cases were detected over 5 years showing an average annual incidence rate of 123.57 per 100,000 persons [age adjusted incidence rate (AAIR)--262/100,000; based on USA population, 1990] and sex-specific AAIR (274/100,000) among women is slightly higher than men (253/100,000). Age-specific stroke incidence rate showed increasing rate from fourth decade up to seventh decade in both sexes when the rate was maximum. First 30 days mortality recorded was 18% with men suffering twice than women. Follow-up after one year revealed speech improvement in 47%, residual spasticity in 46% and independency in activities daily living in 62% of cases. Age and sex matched case control study has shown that hypertension (OR - 2.79), heart disease (OR - 6.20) and smoking (OR - 3.92) are significant risk factors. This study had indicated a higher age adjusted incidence rate of stroke in India as compared to that of developed country and hypertension, heart disease and smoking are important risk factors.

Nutritional factors and susceptibility to arsenic-caused skin lesions in West Bengal, India.

There has been widespread speculation about whether nutritional deficiencies increase the susceptibility to arsenic health effects. This is the first study to investigate whether dietary micronutrient and macronutrient intake modulates the well-established human risk of arsenic-induced skin lesions, including alterations in skin pigmentation and keratoses. The study was conducted in West Bengal, India, which along with Bangladesh constitutes the largest population in the world exposed to arsenic from drinking water. In this case-control study design, cases were patients with arsenic-induced skin lesions and had < 500 microg/L arsenic in their drinking water. For each case, an age- and sex-matched control was selected from participants of a 1995-1996 cross-sectional survey, whose drinking water at that time also contained < 500 microg/L arsenic. Nutritional assessment was based on a 24-hr recall for major dietary constituents and a 1-week recall for less common constituents. Modest increases in risk were related to being in the lowest quintiles of intake of animal protein [odds ratio (OR) = 1.94; 95% confidence interval (CI), 1.05-3.59], calcium (OR = 1.89; 95% CI, 1.04-3.43), fiber (OR = 2.20; 95% CI, 1.15-4.21), and folate (OR = 1.67; 95% CI, 0.87-3.2). Conditional logistic regression suggested that the strongest associations were with low calcium, low animal protein, low folate, and low fiber intake. Nutrient intake was not related to arsenic exposure. We conclude that low intake of calcium, animal protein, folate, and fiber may increase susceptibility to arsenic-caused skin lesions. However, in light of the small magnitude of increased risks related to these dietary deficiencies, prevention should focus on reducing exposure to arsenic.

Mechanism of regulation of phosphorylation-dephosphorylation of Ca2+, Mg2+ and Ca2+ -Atpases by modulator proteins isolated from rat brain cytosol.

Two proteins of molecular mass 13 kDa, a specific inhibitor of Na+, K+ -ATPase and another of 12 kDa, which can distinguish between Ca2, Mg2+ and Ca2+ -ATPase activities have been obtained from the pooled fractions isolated from rat brain, using Sephadex G-100 chromatography. In order to determine the key step(s), which is affected by the modulators, we have designed an in vitro experiment of phosphorylation and dephosphorylation of these ATPases in the absence and presence of the modulators. The results suggest that the phosphorylation step of Mg2+ -independent Ca2+ -ATPase is inhibited, while in Mg2+ -dependent Ca2 -ATPase, the dephosphorylation step is stimulated by the modulators. The findings support our earlier observation that the modulators are able to distinguish between Mg2+ -independent and dependent Ca2+ -ATPases activities.

Development of a new head and neck cancer-specific comorbidity index.

BACKGROUND: Most patients with head and neck squamous cell carcinoma are older and may have coexistent or comorbid diseases. OBJECTIVES: To determine the prognostic impact of individual comorbid conditions in patients with head and neck cancer, to combine the individual comorbid conditions to form a new a head and neck-specific comorbidity instrument, and to compare it with the Modified Kaplan-Feinstein Index to determine if the new disease-specific instrument offers any improvement in survival prediction over a general comorbidity index. DESIGN: Retrospective review of medical records. POPULATION: The study population comprised 1153 patients with biopsy-proven, newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, or larynx. RESULTS: Seven comorbid conditions (congestive heart disease, cardiac arrhythmia, peripheral vascular disease, pulmonary disease, renal disease, cancer controlled, and cancer uncontrolled) were significantly related to survival. These comorbid conditions were assigned integer weights to reflect their relative prognostic importance and combined to create the new Washington University Head and Neck Comorbidity Index (WUHNCI). Survival was significantly related to levels of comorbidity severity as defined by the WUHNCI. The WUHNCI predicted survival better than the Modified Kaplan-Feinstein Index despite containing far fewer ailments. CONCLUSIONS: Comorbidity is an important feature of the patient with head and neck cancer. The WUHNCI can be used for retrospective review or prospective outcomes research.

Factors Influencing Smoking Behavior Among Adolescents.

Objective: To study the impact of tobacco advertisements and other social factors on the smoking habits of adolescents in Calcutta, India. Design: Cross sectional, school based survey of students in the IXth and XIth grades. The responses were analyzed by binary logistic regression. Participants: High School students in Calcutta aged 14 to 18 years. Main Outcome Measure: Smoking Status as defined by ever smokers of tobacco products. Results: 1973 students were interviewed (males-73.79% and females-26.21%). Increased tobacco use was associated with older age-groups, male gender, government-run schools, having parents or peers who were smokers, and if the respondent was also a chewer. The likelihood of a respondent being a smoker was 8.5 times greater (95% CI: 5.05-14.43) if he or she had a smoker friend, and about 4.5 times (95% CI: 2.7-7.4) if he or she had a smoker sibling. In the multivariate model, the parents' smoking status did not have a statistically significant association with respondent's smoking status. Television advertisements of tobacco products had no statistically significant association with respondents' smoking status. Conclusions: The finding of tobacco advertisements not having a significant association with smoking habits among adolescents could be due to the fact that, at the time of this survey, tobacco advertisements were not frequent in the prime channels due to Government regulations. Peer influence had the strongest association with adolescent smoking. It is therefore suggested that the peer influence factor should be considered for anti-tobacco regulatory activities that target adolescent smoking in India.