Long-term medication for ADHD (LMA) trial: 2-year prospective observational study in children and adolescents. Core symptoms, daily functioning, and comorbidity outcomes.

More knowledge is needed about long-term ADHD medication and symptom, daily functioning, comorbidity, and tolerability outcomes. This "Long-term Medication for ADHD (LMA) trial" was a prospective observational 2-year trial in children and adolescents aged 6-18 years (extension of 1-year trial). Participants met criteria for DSM-5 ADHD (inattentive or combined), with complex comorbidities; autism spectrum disorder (31%), autistic traits (24%), oppositional symptoms (59%), anxiety (32%), dyslexia/language disorder (16%), borderline intellectual functioning (17%). Medication was individually tailored and followed-up at clinical visits (1, 2, 3, 6, 12, 18, 24 months). Primary outcome: Clinical Global Impression-Severity and Improvement scales (CGI-S, CGI-I). Secondary outcomes: Investigator-rated ADHD-Rating Scale, Weiss Functional Impairment Rating Scale-Parent report (WFIRS-P; Family, School Learning and Behavior, Life Skills, Self-Concept, Social Activities, and Risky Activities domains), comorbidity symptoms and adverse events (AEs). One hundred twenty-eight participants were enrolled (1-year trial only n = 27, LMA trial n = 101). Of these 29 (23%) discontinued, mainly due to AEs (n = 7), moving (n = 7), or no longer needing medication (n = 6). Main AEs were poor appetite, low mood, anxiety, irritability, fatigue. Improvements from baseline to 2 years were large in CGI-S (effect size (ES) 2.28), ADHD-RS (ES 2.06), and moderate to large in WFIRS-P (ES total 0.73, learning 0.4, family 0.67). Overall, the trial showed robust and sustained improvements in ADHD symptom severity and daily functioning over a period of 2 years of ADHD medication in children and adolescents with ADHD and complex comorbidities. Most AEs were mild. Comorbidity symptoms were improved after 1 year, particularly oppositional symptoms, depression, and anxiety.

RECOMMENDATIONS FOR USE AND SCORING OF ORAL HEALTH IMPACT PROFILE VERSIONS.

BACKGROUND: OHIP's original seven-domain structure does not fit empirical data, but a psychometrically sound and clinically more plausible structure with the four OHRQoL dimensions Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact has emerged. Consequently, use and scoring of available OHIP versions need to be revisited. AIM: We assessed how well the overall construct OHRQoL and its four dimensions were measured with several OHIP versions (20, 19, 14, and 5 items) to derive recommendations which instruments should be used and how to score them. METHODS: Data came from the "Dimensions of OHRQoL Project" and used the project's learning sample (5,173 prosthodontic patients and general population subjects with 49-item OHIP data). We computed correlations among OHIP versions' summary scores. Correlations between OHRQoL dimensions, on one hand, and OHIP versions' domain scores or OHIP-5's items, on the other hand, were also computed. OHIP use and scoring recommendations were derived for psychometrically solid but also practical OHRQoL assessment. RESULTS: Summary scores of 5-, 14-, 19- and 49-item versions correlated highly (r = 0.91-0.98), suggesting similar OHRQoL construct measurement across versions. The OHRQoL dimensions Oral Function, Orofacial Pain, Orofacial Appearance, and Psychosocial Impact were best measured by the OHIP domain scores for Physical Disability, Physical Pain, Psychological Discomfort, and Handicap, respectively. CONCLUSION: Recommendations were derived which OHIP should be preferably used and how OHIP versions should be scored to capture the overall construct and the dimensions of OHRQoL. Psychometrically solid and practical OHRQoL assessment in all settings across all oral health conditions can be achieved with the 5-item OHIP.

Exhaled particles and small airways.

BACKGROUND: Originally, studies on exhaled droplets explored properties of airborne transmission of infectious diseases. More recently, the interest focuses on properties of exhaled droplets as biomarkers, enabled by the development of technical equipment and methods for chemical analysis. Because exhaled droplets contain nonvolatile substances, particles is the physical designation. This review aims to outline the development in the area of exhaled particles, particularly regarding biomarkers and the connection with small airways, i e airways with an internal diameter < 2 mm. MAIN BODY: Generation mechanisms, sites of origin, number concentrations of exhaled particles and the content of nonvolatile substances are studied. Exhaled particles range in diameter from 0.01 and 1000 µm depending on generation mechanism and site of origin. Airway reopening is one scientifically substantiated particle generation mechanism. During deep expirations, small airways close and the reopening process produces minute particles. When exhaled, these particles have a diameter of < 4 µm. A size discriminating sampling of particles < 4 µm and determination of the size distribution, allows exhaled particle mass to be estimated. The median mass is represented by particles in the size range of 0.7 to 1.0 µm. Half an hour of repeated deep expirations result in samples in the order of nanogram to microgram. The source of these samples is the respiratory tract ling fluid of small airways and consists of lipids and proteins, similarly to surfactant. Early clinical studies of e g chronic obstructive pulmonary disease and asthma, reported altered particle formation and particle composition. CONCLUSION: The physical properties and content of exhaled particles generated by the airway reopening mechanism offers an exciting noninvasive way to obtain samples from the respiratory tract lining fluid of small airways. The biomarker potential is only at the beginning to be explored.

Better survival for patients with colon cancer operated on by specialized colorectal surgeons - a nationwide population-based study in Sweden 2007-2010.

AIM: Mortality and complication rates after surgery for colon cancer are high, especially after emergency procedures. The aim of the present study was to evaluate the importance of the formal competence of surgeons for survival and morbidity. METHOD: The Swedish Colorectal Cancer Registry prospectively records data on patients diagnosed with cancer within the colon and rectum. A cohort of patients operated on for colon cancer between 2007 and 2010 were followed 5 years after surgery. Data on postoperative morbidity, mortality and long-term survival were compared with regard to formal competency of the most senior surgeon attending the procedure. RESULTS: This analysis includes 13 365 patients operated on for colon cancer, including 10 434 elective procedures and 2931 emergency cases. The overall 5-year survival was higher for those operated on by subspecialist colorectal surgeons compared with general surgeons (60% vs 48%; P < 0.001). Five-year survival after elective surgery was 63% vs 55% (P < 0.001) and 35% vs 31% (P < 0.05) after emergency procedures when performed by colorectal surgeons compared with general surgeons. Postoperative 30-day mortality was 3% after surgery performed by colorectal surgeons compared with 7% when performed by general surgeons. Mortality at 90 days was 6% after surgery performed by colorectal surgeons compared with 11% for patients operated on by general surgeons (P < 0.001). CONCLUSION: Subspecialization in colorectal surgery is associated with better outcome for patients operated on for colon cancer, and effort should be made to increase the availability of colorectal surgeons for both acute and elective colon cancer surgery.

Complications related to induced abortion: a combined retrospective and longitudinal follow-up study.

BACKGROUND: Induced abortion is one of the most common gynecological procedures in Sweden, but there is still little knowledge about the adverse effects. The aims of this study are to provide an overview of complications of medical and surgical abortions and to evaluate the impact of bacterial screening to prevent postabortal infections. METHODS: All women who underwent induced abortion at Skaraborg Hospital between 2008 and 2015 are included in the study. Bacterial screening for chlamydia, gonorrhea, mycoplasma, and bacterial vaginosis was performed prior to the abortions. Abortion complications, categorized as bleeding, infection, or incomplete abortion were assessed in women who came in contact with the gynecological clinic within 30 days after the procedure. RESULTS: A total of 4945 induced abortions were performed during the study period. Nearly all, 4945 (99.7%) were eligible for inclusion in the study. Medical abortions < 12 weeks were the most common procedure (74.7%), followed by surgical abortions (17.5%), and medical abortion > 12 weeks (7.8%). Complications were registered in 333 (6.7%) of all abortions. Among medical abortions < 12 weeks, the complication frequency increased significantly, from 4.2% in 2008 to 8.2% in 2015 (RR 1.49, 95% 1.04-2.15). An incomplete abortion was the most common complication related to medical abortions < 12 weeks. Of all women who tested positive for one or several bacteria at the screening and therefore received antibiotics, 1.4% developed a postabortal infection. Among those who tested negative at the screening, 1.7% developed infectious complications. CONCLUSIONS: The share of complications related to medical abortions < 12 weeks increased significantly during 2008-2015 without any evident cause. Women who tested positive for one or several bacteria upon screening and received antibiotics experienced almost an equal proportion of postabortal infections compared to women who tested negative upon screening. The screening process seems to fulfill its purpose of reducing the risk of infectious complications.

Prevalence and oral health-related quality of life of self-reported orofacial conditions in Sweden.

OBJECTIVES: To (i) determine the prevalences of self-report in a Swedish adult population, of temporomandibular disorders, burning mouth syndrome, dry mouth, and bad breath and (ii) determine oral health-related quality-of-life impairment in subjects reporting these conditions. SUBJECTS AND METHODS: A cross-sectional, randomized sample of the adult Swedish population (response rate: 46%, N = 1309 subjects) self-reported their condition from the preceding month to assess prevalences of self-report for the studied conditions together with comorbidity group of subjects who reported more than one condition. The 49-item Oral Health Impact Profile (OHIP) used to assess oral health-related quality of life. RESULTS: The most prevalent condition was bad breath (39%), followed by dry mouth (22%), temporomandibular disorders (18%) and burning mouth syndrome (4%). High comorbidity of conditions occurred in 27% of the population. Quality-of-life impairment increased with the number of comorbid conditions. Among individual conditions, burning mouth syndrome and temporomandibular disorders (57% and 40% OHIP points) presented higher impairment than dry mouth and bad breath (32% and 26% OHIP points). CONCLUSIONS: Orofacial conditions were common and often coexist. The comorbidity group experienced the highest impact on oral health-related quality of life: the more the comorbid conditions, the greater the negative impact.

Patterns of impaired oral health-related quality of life dimensions.

How dental patients are affected by oral conditions can be described with the concept of oral health-related quality of life (OHRQoL). This concept intends to make the patient experience measurable. OHRQoL is multidimensional, and Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact were suggested as its four dimensions and consequently four scores are needed for comprehensive OHRQoL assessment. When only the presence of dimensional impact is measured, a pattern of affected OHRQoL dimensions would describe in a simple way how oral conditions influence the individual. By determining which patterns of impact on OHRQoL dimensions exist in prosthodontic patients and general population subjects, we aimed to identify in which combinations oral conditions' functional, painful, aesthetical and psychosocial impact occurs. Data came from the Dimensions of OHRQoL Project with Oral Health Impact Profile (OHIP)-49 data from 6349 general population subjects and 2999 prosthodontic patients in the Learning Sample (N = 5173) and the Validation Sample (N = 5022). We hypothesised that all 16 patterns of OHRQoL dimensions should occur in these individuals who suffered mainly from tooth loss, its causes and consequences. A dimension was considered impaired when at least one item in the dimension was affected frequently. The 16 possible patterns of impaired OHRQoL dimensions were found in patients and general population subjects in both Learning and Validation Samples. In a four-dimensional OHRQoL model consisting Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact, oral conditions' impact can occur in any combination of the OHRQoL dimensions.

Psychometric properties of the Dutch version of the Orofacial Esthetic Scale (OES-NL) in dental patients with and without self-reported tooth wear.

The aim of this study was to test the psychometric properties of the Dutch version of the Orofacial Esthetic Scale (OES) in dental patients with and without self-reported tooth wear. The English version of the OES was translated into Dutch, following established guidelines for cross-cultural adaptation of health-related quality of life measures. The reliability of the resulting OES-NL was tested in a test-retest study on 343 subjects; its validity was tested with the use of convergent validity on 582 subjects. The test-retest reliability of the OES-NL showed intra-class correlation coefficients (ICC) that ranged from 0·76 to 0·82, which can be qualified as excellent. The Cronbach's alpha revealed that the overall internal consistency of the scale was good (α = 0·89). Convergent validity was confirmed by the association between the OES-NL summary scores and three questions of the Dutch version of the Oral Health Impact Profile (OHIP-NL). The calculated Spearman's rank correlation coefficients ranged from -0·43 to -0·54 and were all significant (P < 0·001). The Dutch version of the Orofacial Esthetic Scale (OES-NL) showed good psychometric properties, making it suitable for the assessment of self-perceived aesthetics in Dutch dental patients with and without self-reported tooth wear.

Pike Esox lucius as an emerging model organism for studies in ecology and evolutionary biology: a review.

The pike Esox lucius is a large, long-lived, iteroparous, top- predator fish species with a circumpolar distribution that occupies a broad range of aquatic environments. This study reports on a literature search and demonstrates that the publication rate of E. lucius research increases both in absolute terms and relative to total scientific output, and that the focus of investigation has changed over time from being dominated by studies on physiology and disease to being gradually replaced by studies on ecology and evolution. Esox lucius can be exploited as a model in future research for identifying causes and consequences of phenotypic and genetic variation at the levels of individuals, populations and species as well as for investigating community processes.

Normative values for the Oro-facial Esthetic Scale in Sweden.

This study reports the findings and challenges of the assessment of oro-facial aesthetics in the Swedish general population and the development of normative values for the self-reporting Orofacial Esthetic Scale (OES). In a Swedish national sample of 1406 adult subjects (response rate: 47%), OES decile norms were established. The influence of sociodemographics (gender, age, and education), oral health status and general health status on OES scores was analysed. Mean ± standard deviation of OES scores was 50.3 ± 15.6 units (0, worst score; 70, best score); <1% of the subjects had the minimum score of 0, and 11% had the maximum score of 70 OES units. Orofacial Esthetic Scale score differences were (i) substantial (>5 OES units) for subjects with excellent/very good versus good to poor oral or general health status; ii) small (2 units), but statistically significant for gender (P = 0.01) and two age groups (P = 0.02), and (iii) absent for subjects with college versus no college education (P = 0.31) or with and without dentures (P = 0.90). To estimate normative values for a self-reporting health status, instrument is considered an important step in standardisation, and the developed norms provide a frame of reference in the general population to interpret the Orofacial Esthetic Scale scores.

General population norms of the Swedish short forms of oral health impact profile.

We reported the development and psychometric evaluation of a Swedish 14-item and a five-item short form of the Oral Health Impact Profile. The 14-item version was derived from the English-language short form developed by Slade in1997. The five-item version was derived from the German-language short form developed by John et al. in 2006. Validity, reliability and normative values for the two short form summary scores were determined in a random sample of the adult Swedish population (response rate: 46%, N = 1366 subjects). Subjects with sufficient OHRQoL information to calculate a summary score (N = 1309) were on average 50·1 ± 17.4 years old, and 54% were women. Short form summary scores correlated highly with the 49-item OHIP-S (r ≥ 0.97 for OHIP-S14, r ≥ 0.92 for OHIP-S5) and with self-report of oral health (r ≥ 0.41). Reliability, measured with Cronbach's alpha (0.91 for OHIP-S14, 0.77 for OHIP-S5), was sufficient. In the general population, 50% of the subjects had ≥2 OHIP-S14 score points and 10% had ≥11 points, respectively. Among subjects with their own teeth only and/or fixed dental prostheses and with partial removable dental prostheses, 50% of the population had ≥2 OHIP-S14 score points, and 10% had ≥11 points. For subjects with complete dentures, the corresponding figures were 3 and 24 points. OHIP-S5 medians for subjects in the three population groups were 1, 1 and 2 points. Swedish 14-item and 5-item short forms of the OHIP have sufficient psychometric properties and provide a detailed overview about impaired OHRQoL in Sweden. The norms will serve as reference values for future studies.

Confirmatory factor analysis of the Oral Health Impact Profile.

Previous exploratory analyses suggest that the Oral Health Impact Profile (OHIP) consists of four correlated dimensions and that individual differences in OHIP total scores reflect an underlying higher-order factor. The aim of this report is to corroborate these findings in the Dimensions of Oral Health-Related Quality of Life (DOQ) Project, an international study of general population subjects and prosthodontic patients. Using the project's Validation Sample (n = 5022), we conducted confirmatory factor analyses in a sample of 4993 subjects with sufficiently complete data. In particular, we compared the psychometric performance of three models: a unidimensional model, a four-factor model and a bifactor model that included one general factor and four group factors. Using model-fit criteria and factor interpretability as guides, the four-factor model was deemed best in terms of strong item loadings, model fit (RMSEA = 0·05, CFI = 0·99) and interpretability. These results corroborate our previous findings that four highly correlated factors - which we have named Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact - can be reliably extracted from the OHIP item pool. However, the good fit of the unidimensional model and the high interfactor correlations in the four-factor solution suggest that OHRQoL can also be sufficiently described with one score.

Exploratory factor analysis of the Oral Health Impact Profile.

Although oral health-related quality of life (OHRQoL) as measured by the Oral Health Impact Profile (OHIP) is thought to be multidimensional, the nature of these dimensions is not known. The aim of this report was to explore the dimensionality of the OHIP using the Dimensions of OHRQoL (DOQ) Project, an international study of general population subjects and prosthodontic patients. Using the project's Learning Sample (n = 5173), we conducted an exploratory factor analysis on the 46 OHIP items not specifically referring to dentures for 5146 subjects with sufficiently complete data. The first eigenvalue (27·0) of the polychoric correlation matrix was more than ten times larger than the second eigenvalue (2·6), suggesting the presence of a dominant, higher-order general factor. Follow-up analyses with Horn's parallel analysis revealed a viable second-order, four-factor solution. An oblique rotation of this solution revealed four highly correlated factors that we named Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact. These four dimensions and the strong general factor are two viable hypotheses for the factor structure of the OHIP.

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice.

AIMS/HYPOTHESIS: Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring. METHODS: The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. RESULTS: Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. CONCLUSIONS/INTERPRETATION: Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes.

Change in Gait Deviation Index after anti-tumour necrosis factor-α treatment in individuals with rheumatoid arthritis: a pilot study.

OBJECTIVES: Anti-tumour necrosis factor-alpha (TNF-α) inhibitors provide fast, effective resolution of rheumatoid arthritis (RA) inflammation. In this study we aimed to quantify the impact of TNF-α treatment on gait dynamics. METHOD: The sample comprised 16 subjects [11 female, median age 56 (range 48-66) years, median disease duration 9.5 (range 4.6-20.6) years] with RA who met the American College of Rheumatology (ACR) criteria, had lower extremity involvement, did not use walking aids, and had started TNF-α treatment within 1 week of baseline gait analysis. Gait analysis focused on three-dimensional (3D) lower extremity joint kinematics, kinetics, time and distance parameters. The Gait Deviation Index (GDI) and GDI-Kinetic were calculated. Data on gait, disease activity, and physical disability were collected at baseline and at 3.5 months. RESULTS: Following treatment with TNF-α, statistically significant improvements were found in disease activity [using the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP); median difference (m(d)) = 2.3, p < 0.01], physical disability [Health Assessment Questionnaire (HAQ) m(d) = 0.4, p < 0.01], and pain during walking [visual analogue scale (VAS) m(d) = 11.0, p < 0.05]. Reductions in gait deviations were noted (GDI m(d) = 3.7, p = 0.04; GDI-Kinetic m(d) = 4.1, p = 0.05) along with reductions in dimensionless time and distance parameters. A moderate to good negative correlation existed between baseline GDI and GDI change scores (r(s) = -0.7, p < 0.01). CONCLUSIONS: Treatment with TNF-α improved gait dynamics in adults with RA. Significant gait deviations were, however, still present after treatment. In this study, GDI and GDI-Kinetic scores appeared to be useful outcome measures to quantify changes in gait deviations after this intervention.

The genes of all seven CYP3A isoenzymes identified in the equine genome are expressed in the airways of horses.

In the present study, we examined the gene expression of cytochrome P450 3A (CYP3A) isoenzymes in the tracheal and bronchial mucosa and in the lung of equines using TaqMan probes. The results show that all seven CYP3A isoforms identified in the equine genome, that is, CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, CYP3A97 and CYP3A129, are expressed in the airways of the investigated horses. Though in previous studies, CYP3A129 was found to be absent in equine intestinal mucosa and liver, this CYP3A isoform is expressed in the airways of horses. The gene expression of the CYP3A isoenzymes varied considerably between the individual horses studied. However, in most of the horses CYP3A89, CYP3A93, CYP3A96, CYP3A97 and CYP3A129 were expressed to a high extent, while CYP3A94 and CYP3A95 were expressed to a low extent in the different parts of the airways. The CYP3A isoenzymes present in the airways may play a role in the metabolic degradation of inhaled xenobiotics. In some instances, the metabolism may, however, result in bioactivation of the xenobiotics and subsequent tissue injury.

Effect of shear stress, statins and TNF-α on hemostatic genes in human endothelial cells.

Atherosclerotic plaque formation and progression are dependent on local shear stress patterns and inflammatory cytokines. Statins effectively reduce the progression of atherosclerosis and the incidence of cardiovascular events. However, the benefit of statins cannot be explained by cholesterol reduction alone. This study, investigated the non-lipid lowering effects of simvastatin and rosuvastatin on endothelial anti- and prothrombotic genes under different biomechanical and inflammatory stress conditions. Endothelial cells responded in a similar way to simvastatin and rosuvastatin. However, they were more sensitive to simvastatin. The statins had anti-inflammatory properties counteracting the TNF-α effect on the hemostatic genes studied. There was no observed synergistic effect between shear stress and simvastatin. Simvastatin had a counteracting effect on t-PA and PAI-1 compared to TNF-α and shear stress. Simvastatin blocked the TNF-α suppressive effect on thrombomodulin and eNOS, irrespective of shear stress. The strong inductive effect of TNF-α on VCAM-1 was counteracted by simvastatin and shear stress in an additive dose-response dependent way.

TOF-SIMS analysis of exhaled particles from patients with asthma and healthy controls.

Particles in exhaled air (PEx) may reflect the composition of respiratory tract lining fluid (RTLF); thus, there is a need to assess their potential as sources of biomarkers for respiratory diseases. In the present study, we compared PEx from patients with asthma and controls using time-of-flight-secondary ion mass spectrometry (TOF-SIMS) and multivariate analysis. Particles were collected using an instrument developed in-house. 15 nonsmoking subjects with physician-diagnosed asthma and 11 nonsmoking healthy controls performed 10 consecutive forced exhalations into the instrument. Particle concentrations were recorded and samples of particles collected on silicon plates were analysed by TOF-SIMS. Subjects with asthma exhaled significantly lower numbers of particles than controls (p=0.03) and the ratio of unsaturated to saturated phospholipids was significantly lower in samples from subjects with asthma (0.25 versus 0.35; p=0.036). Orthogonal partial least squares-discriminant analysis models showed good separation between both positive and negative spectra. Molecular ions from phosphatidylcholine and phosphatidylglycerol, and protein fragments were found to discriminate the groups. We conclude that analysis of PEx is a promising method to examine the composition of RTLF. In the present explorative study, we could discriminate between subjects with asthma and healthy controls based on TOF-SIMS spectra from PEx.

Application of a computational model of vagus nerve stimulation.

OBJECTIVES: The most widely used and studied neurostimulation procedure for medically refractory epilepsy is vagus nerve stimulation (VNS) Therapy. The goal of this study was to develop a computational model for improved understanding of the anatomy and neurophysiology of the vagus nerve as it pertains to the principles of electrical stimulation, aiming to provide clinicians with a systematic and rational understanding of VNS Therapy. MATERIALS AND METHODS: Computational modeling allows the study of electrical stimulation of peripheral nerves. We used finite element electric field models of the vagus nerve with VNS Therapy electrodes to calculate the voltage field for several output currents and studied the effects of two programmable parameters (output current and pulse width) on optimal fiber activation. RESULTS: The mathematical models correlated well with strength-duration curves constructed from actual patient data. In addition, digital constructs of chronic versus acute implant models demonstrated that at a given pulse width and current combination, presence of a 110-µm fibrotic tissue can decrease fiber activation by 50%. Based on our findings, a range of output current settings between 0.75 and 1.75 mA with pulse width settings of 250 or 500 µs may result in optimal stimulation. CONCLUSIONS: The modeling illustrates how to achieve full or nearly full activation of the myelinated fibers of the vagus nerve through output current and pulse width settings. This knowledge will enable clinicians to apply these principles for optimal vagus nerve activation and proceed to adjust duty cycle and frequency to achieve effectiveness.

Differential gene expression of CYP3A isoforms in equine liver and intestines.

Recently, seven CYP3A isoforms - CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, CYP3A97 and CYP129 - have been isolated from the horse genome. In this study, we have examined the hepatic and intestinal gene expression of these CYP3A isoforms using TaqMan probes. We have also studied the enzyme activity using luciferin-isopropyl acetal (LIPA) as a substrate. The results show a differential gene expression of the CYP3A isoforms in the liver and intestines in horses. In the liver, CYP3A89, CYP3A94, CYP3A96 and CYP3A97 were highly expressed, while in the intestine there were only two dominating isoforms, CYP3A93 and CYP3A96. The isoform CYP3A129 was not detected in the liver or the intestine, although this gene consists of a complete set of exons and should therefore code for a functional protein. It is possible that this gene is expressed in tissues other than the liver and intestines. In the intestine, both CYP3A96 and CYP3A93 showed the highest gene expression in the duodenum and the proximal parts of the jejunum. This correlated with a high protein expression in these tissues. Studies of the enzyme activity showed the same K(m) for the LIPA substrate in the liver and the intestine, while the maximum velocity (V(max)) in the liver was higher than in the intestine. Our finding of a differential gene expression of the CYP3A isoforms in the liver and the intestines contributes to a better understanding of drug metabolism in horses.