Search

Introduction: There are no standard targeted treatment options for advanced KRAS-mutant NSCLC beyond KRAS G12C inhibitors. A computational model identified regorafenib and low-dose methotrexate as synergistic in preclinical models of KRAS-mutant NSCLC. This study evaluated the efficacy and safety of the combination in previously treated advanced KRAS-mutant NSCLC. Methods: This single-arm phase II study included regorafenib 80 to 120 mg oral daily and oral methotrexate dose escalated to tolerability from 10 to 20 mg twice weekly during the first cycle. Both agents were administered on weeks 1 to 3 of each 4-week cycle. The primary end point was progression-free survival. Results: In total, 18 patients with KRAS-mutant NSCLC were enrolled. Five patients received regorafenib at a 120 mg starting dose with four discontinuing due to toxicity; subsequently, 13 patients were treated at an 80 mg starting dose, with eight dose-escalating to 120 mg after the first cycle. Median progression-free survival was 3.7 months (95% confidence interval 1.8–8.6) and median overall survival was 10.4 months (95% confidence interval 5.2–30.3). The objective response rate was 16.7% and the 8-week disease control rate was 66.7%. Grade 3 treatment-related adverse events occurred in 11 patients, most often oral mucositis (n = 2) and asymptomatic lipase increase (n = 2). One patient developed asymptomatic grade 4 lipase increase. Conclusions: Combination treatment of regorafenib and oral methotrexate in patients with KRAS-mutant NSCLC was limited due to toxicity, and the study did not meet its primary end point. Computational modeling may aid in repurposing therapeutic options though caution must be exercised with tolerability.

Background: Cerebral palsy (CP) is a group of nonprogressive disorders of movement and posture caused by abnormal development of, or damage to, motor control centers of the brain. A single nucleotide polymorphism (SNP), rs1800795, in the promoter region of

BackgroundPediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions.Objectives and methodsThe objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array.Results and discussionWe identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS.ConclusionsThis is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

EXECUTIVE SUMMARY- Iowa was a tobacco control leader in the 19th Century. In 1897 the General Assembly completely prohibited the use, sale, and possession of tobacco products in the state. When the law was repealed in 1921, the General Assembly enacted strong measures to prevent tobacco use by minors. In 1921 Iowa passed the first state cigarette excise tax (2 cents).- Tobacco control reemerged in the 1970s, however a coalition of health groups were consistently outmaneuvered by tobacco industry lobbyists.- In 1990 health groups attempted to strengthen Iowa’s Clean Indoor Air Act (passed in 1987), however the tobacco industry, represented primarily by Charles Wasker, co-opted the bill, stripping meaningful tobacco control provisions and using it to include ambiguous language to preempt localities from passing clean indoor air laws, which chilled local clean indoor air action for a decade.- In 1993 the voluntary health organizations founded Tobacco Free Iowa (TFI), a dedicated statewide tobacco control coalition to advocate for tobacco control policy change. In 1995 TFI hired Serge Garrison, a former R.J. Reynolds (RJR) lobbyist, to lobby to repeal clean indoor air preemption. Garrison, who helped draft the preemption clause when working for RJR, questioned whether Iowa’s ambiguously worded clause actually preempted local clean indoor air action.- Iowa, represented by Attorney General Tom Miller (D), was a party in the 1998 Master Settlement Agreement. Miller and the Iowa Attorney General’s Office, have been strong allies to tobacco control in Iowa.- After the MSA, in 2000, Iowa created the Division of Tobacco Use Prevention and Control within the Iowa Department of Public Health to implement a state tobacco control program funded with MSA revenue.- In 2001 the General Assembly passed legislation to securitize the MSA revenue stream to receive an upfront lump sum in lieu of most future MSA payments. Politicians framed MSA securitization as a way to create stable funding for health programs, including tobacco, but the vast majority of the money went to infrastructure projects.- The Health Iowans Tobacco Trust created through securitization to fund tobacco and other health programs was continually raided by the General Assembly from 2001 to 2008, and zeroed out in 2009.- The Iowa Tobacco Division has never been funded at or near the CDC recommended best practices for tobacco control and tobacco control advocates have not mobilized enough political pressure to demand and protect funding for the Tobacco Division.- From 1998 to 2008, $44,577 in campaign contributions were given to Iowa legislative candidates and party committees by five tobacco companies: Altria/Philip Morris, Farner-Bocken (an Iowa-based distributor), Myers-Cox Company (an Iowa-based distributor),R.J. Reynolds, and US Smokeless Tobacco.- Tobacco industry contributions spiked in 2000 when the Iowa General Assembly was considering legislation to create the Iowa Tobacco Division and deciding the use of their MSA payments. Contributions dropped in 2004 after the General Assembly mandated that the Tobacco Division have a youth focus (a pro-industry position) and securitized most of their MSA revenue. In 2004, industry contributions jumped back up (and steadily increased though 2008) concurrent with an increase in the introduction of tobacco control initiatives (which were repeatedly killed until 2007).- The tobacco industry focused contributions on legislative leaders. Rep. Christopher Rants(R-Woodbury) former Iowa House Majority Leader (1999-2003) and Speaker of the House (2003-2006) received the most industry money from 1998-2008 ($7,397). Rants was a key player in killing tobacco tax and local control bills throughout the 2000s. Representative Jamie Van Fossen (R- Scott) who served as the Chair of the House Ways and Means Committee received the second greatest amount ($6,050), followed by Sen. Stewart Iverson, Jr. (R-Wright), Senate Majority Leader from 1997-2006 ($2,220).- From 1998 to 2008, tobacco industry contributions to Republican candidates and the Republican party ($27,947) far outweighed contributions to their Democratic counterparts($15,130). From 1998 to 2007, Republicans controlled both houses (except in 2006 when the Senate was tied).- Republican legislators were significantly more pro-tobacco than Democrats.- Legislators who accepted campaign contributions from the tobacco industry were significantly more pro-tobacco than those who did not, controlling for party.- The tobacco industry maintains a significant lobbying presence, between 2003 and 2008 the tobacco industry reported $667,875 in lobbying expenditures in Iowa.- After an inquiry prompted by Serge Garrison in the late 1990s, Attorney General Tom Miller (D) issued an opinion in November 2000 stating that state law did not preempt local clean indoor air ordinances.- From 1999 to 2003 there was a tide of local clean indoor air action. In March 2002, Ames passed Iowa’s first clean indoor air ordinance. Ames’ ordinance included a tobacco industry inspired “hours” provision that allowed smoking after 8:30pm, advocated for by hospitality interests, making the ordinance weak. Its passage created momentum for other localities to pass clean indoor air measures.- In January 2002, Iowa City passed Iowa’s first 100% smokefree restaurant ordinance. Other localities, aided by the Iowa Attorney General’s Office and TFI, began considering ordinances and enactment of voluntary clean indoor air policies.- Local clean indoor air progress was blocked in 2003, after a group of Ames business owners, funded by Philip Morris, challenged the Ames ordinance in court. In May 2003, the Iowa Supreme Court ruled that the 1990 Clean Indoor Air Act was preemptive.- In 2003, TFI collapsed, leaving Iowa without a functioning tobacco control coalition until 2006. In 2003 some advocates reorganized to create CAFE Iowa and CAFE Iowa CAN, primarily to repeal preemption.- Beginning in 2005, under the direction of Iowa Tobacco Division Director Bonnie Mapes, Iowa advocates reorganized and created a strategic plan. In 2006 the Iowa Tobacco Prevention Alliance was created to assume the role of Iowa’s statewide tobacco control coalition.- The combination Democrats taking control of the legislature in 2007 and the reorganization of tobacco control advocates in 2006 led to substantial tobacco control policy changes.- In 2007 the Iowa General Assembly passed a $1 increase in the cigarette tax, the first increase in 16 years.- In 2008 the General Assembly passed the strong Iowa Smokefree Air Act that extended smokefree environments to 99 percent of Iowa employees and repealed preemption.- Following the 2007 tax increase, adult smoking rates in Iowa fell from 18 to 14% in two years (2006 to 2008).- Youth smoking rates increased from 2004 to 2006 following a substantial cut in allocations to the Tobacco Division in 2002, leading to a substantial decrease in expenditures for Just Eliminate Lies, Iowa’s youth counter-marketing campaign.- Tobacco control advocates must make securing and maintain adequate funding for Iowa’s Tobacco Division a top priority. The CDC recommends that tobacco control programs in Iowa be funded at $36.7 million per year. In FY 2009, the Tobacco Division received only $11.0 million, less than a third of the CDC recommended level. An increase in funding is particularly important because of the increase in youth smoking rates since JEL’s 2002 funding cut.- Given the Tobacco Division’s limited budget and the increasing levels of youth and young adult smoking, the Tobacco Division should focus less on funding individual level cessation services (other than the Quitline, which is a public health intervention) and instead increase its emphasis on media and community-based programs that are more cost effective public health interventions to reduce tobacco use.- Advocates should work to require health insurance to provide cessation services through the medical services budget, not public health.- Advocates need to expand their base beyond major cities to rural areas of Iowa to broaden the base of support for smokefree environments and expand the political base to maintain and expand funding for tobacco control efforts.

Satellite monitoring of icebergs in the Arctic region is paramount for the safety of shipping and maritime activities. The potential of polarimetric synthetic aperture radar data in enhancing detection capabilities of icebergs under interchangeable and challenging conditions is explored in this work. We introduce RADARSAT-2 quad-pol C-band data to detect icebergs in Kongsfjorden, Svalbard. The location contains two tidewater glaciers and is chosen because multiple processes are present in this region, such as ice formation and its relationship with the glaciers, freshwater discharge. Six state-of-the-art detectors are tested for detection performance. These are the dual-intensity polarization ratio anomaly detector, polarimetric notch filter, polarimetric match filter, symmetry, polarimetric whitening filter (PWF), and optimal polarimetric detector (OPD). In addition, we also tested the parameters of the Cloude–Pottier decomposition. In this study, we make use of a ground-based radar for validation and comparison with satellite images. We show that in calm sea-state conditions, the OPD and PWF detectors give high probability of detection (PD) values of 0.7–0.8 when the probability of false alarm (PF) value is 0.01–0.05, compared with choppy sea conditions where the same detectors have degraded performance (PD = 0.5–0.7). Target-to-clutter ratio (TCR) values for each polarization channel is also extracted and compared to the icebergs’ dimensions. The ground-based radar shows higher values in TCR, compared with satellite images. These findings corroborate previous work and show that sea-ice activity, surface roughness, incidence angle, weather, and sea-state conditions all affect the sensitivity of the detectors for this task.

This study evaluated the influence of acute water ingestion and maintaining an upright posture on raw bioimpedance and subsequent estimates of body fluids and composition. Twenty healthy adults participated in a randomized crossover study. In both conditions, an overnight food and fluid fast was followed by an initial multi-frequency bioimpedance assessment (InBody 770). Participants then ingested 11 mL/kg of water (water condition) or did not (control condition) during a 5-minute period. Thereafter, bioimpedance assessments were performed every 10 minutes for one hour with participants remaining upright throughout. Linear mixed effects models were used to examine the influence of condition and time on raw bioimpedance, body fluids, and body composition. Water consumption increased impedance of the arms but not trunk or legs. However, drift in leg impedance was observed, with decreasing values over time in both conditions. No effects of condition on body fluids were detected, but total body water and intracellular water decreased by ~0.5 kg over time in both conditions. Correspondingly, lean body mass did not differ between conditions but decreased over the measurement duration. The increase in body mass in the water condition was detected exclusively as fat mass, with final fat mass values ~1.3 kg higher than baseline and also higher than the control condition. Acute water ingestion and prolonged standing exert practically meaningful effects on relevant bioimpedance variables quantified by a modern, vertical multi-frequency analyzer. These findings have implications for pre-assessment standardization, methodological reporting, and interpretation of assessments.

We consider estimation and variable selection in the partial linear model for censored data. The partial linear model for censored data is a direct extension of the accelerated failure time model, the latter of which is a very important alternative model to the proportional hazards model. We extend rank-based lasso-type estimators to a model that may contain nonlinear effects. Variable selection in such partial linear model has direct application to high-dimensional survival analyses that attempt to adjust for clinical predictors. In the microarray setting, previous methods can adjust for other clinical predictors by assuming that clinical and gene expression data enter the model linearly in the same fashion. Here, we select important variables after adjusting for prognostic clinical variables but the clinical effects are assumed nonlinear. Our estimator is based on stratification and can be extended naturally to account for multiple nonlinear effects. We illustrate the utility of our method through simulation studies and application to the Wisconsin prognostic breast cancer data set. [ABSTRACT FROM AUTHOR]

Risk drinking, especially binge drinking, and unprotected sex may co-occur in college women and increase the risks of STI exposure and pregnancy, but the relationships among these behaviors are incompletely understood. A survey was administered to 2012 women of ages 18-24 enrolled in a public urban university. One-quarter of the college women (23%) drank eight or more drinks per week on average, and 63% binged in the past 90 days, with 64% meeting criteria for risk drinking. Nearly all sexually active women used some form of contraception (94%), but 18% used their method ineffectively and were potentially at risk for pregnancy. Forty-four percent were potentially at risk for STIs due to ineffective or absent condom usage. Ineffective contraception odds were increased by the use of barrier methods of contraception, reliance on a partner's decision to use contraception, and risk drinking, but were decreased by the use of barrier with hormonal contraception, being White, and later age to initiate contraception. In contrast, ineffective condom use was increased by reliance on a partner's decision to use condoms, the use of condoms for STI prevention only, and by risk drinking. Thirteen percent of university women were risk drinkers and using ineffective contraception, and 31% were risk drinkers and failing to use condoms consistently. Risk drinking is related to ineffective contraception and condom use. Colleges should promote effective contraception and condom use for STI prevention and consider coordinating their programs to reduce drinking with programs for reproductive health. Emphasizing the use of condoms for both pregnancy prevention and STI prevention may maximize women's interest in using them. [ABSTRACT FROM AUTHOR]

Context: Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system.Objective: To determine if topiramate is a safe and efficacious treatment for alcohol dependence.Design, Setting, and Participants: Double-blind, randomized, placebo-controlled, 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence, conducted between January 27, 2004, and August 4, 2006, at 17 US sites.Interventions: Up to 300 mg/d of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.Main Outcome Measures: Primary efficacy variable was self-reported percentage of heavy drinking days. Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) along with the laboratory measure of alcohol consumption (plasma gamma-glutamyltransferase).Results: Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval, 3.07%-13.80%; P = .002). Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79%-21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons). Adverse events that were more common with topiramate vs placebo, respectively, included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).Conclusion: Topiramate is a promising treatment for alcohol dependence.Trial Registration: clinicaltrials.gov Identifier: NCT00210925. [ABSTRACT FROM AUTHOR]

Context--Recent modifications to the QLTP (Questionnaire for Lung Transplant Patients), including changing items from dichotomous to multiple dimension scaling, adding psychological symptoms, and converting to an electronic format (e-QLTP), made it necessary to reevaluate its reliability, validity, recipient satisfaction, and feasibility of administering the e-QLTP in the clinical setting. Purpose--To report the final modifications, psychometric properties, recipient satisfaction, and feasibility of administering the e-QLTP, a patient report outcome measure of symptoms and activity tolerance. Methods--Sixty lung recipients completed the original QLTP and the e-QLTP and rated their satisfaction with the e-version during a routine posttransplant evaluation; 65% (38 of 60) also completed a retest version. Correlations were computed for retest stability, concurrent validity between versions of the QLTP, and construct validity among the subscales of the e-QLTP and forced expiratory volumes in 1 second. Using the After Scenario Questionnaire, participants rated their satisfaction with the ease, amount of time, and support information when completing the e-QLTP. Results--The e-QLTP and subscales were internally consistent ([alpha]=.73-.90) and stable (intraclass correlations = .47-.93). Significant correlations (P=.001) were found between the e-QLTP and the original QLTP (r=0.53-0.56) and between the e-QLTP subscales and forced expiratory volumes in 1 second (r=0.51-0.53). The overall mean satisfaction score was 1.27 (± 0.47). Conclusions--The e-QLTP is a reliable and valid measure of physical and psychological symptoms after lung transplantation. It is feasible to complete in the clinical setting and recipients are highly satisfied with its use. Its computerized functionality enhances assessment and management of symptoms over time. [ABSTRACT FROM AUTHOR]

Context: Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.Objectives: To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and Participants: Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.Interventions: Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.Main Outcome Measures: Percent days abstinent from alcohol and time to first heavy drinking day.Results: All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone x behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.Conclusions: Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.Trial Registration: clinicaltrials.gov Identifier: NCT00006206. [ABSTRACT FROM AUTHOR]

This article represents the proceedings of a symposium presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, on September 30, 2004. The organizers and cochairs were Bankole A. Johnson, DSc, MD, PhD, and Karl Mann, MD. The presentations included the following: (1) A Perspective from Academia, by Bankole A. Johnson, DSc, MD, PhD; (2) A Perspective from NIAAA, by Mark L. Willenbring, MD; (3) A Perspective from US Clinical Practice, by Robert M. Swift, MD, PhD; (4) A European Perspective on Medications Development, by Otto M. Lesch, MD, PhD, and (5) A Scandinavian Perspective on Evidence-Based Addiction Treatment, by Mats Berglund, MD. [ABSTRACT FROM AUTHOR]

This article represents the proceedings of a symposium presented at the 12th Congress of the International Society for Biomedical Research on Alcoholism held in Heidelberg/Mannheim, Germany, on October 1, 2004. The organizers and cochairs were Nassima Ait-Daoud, MD, and Gerhard A. Wiesbeck, MD. The presentations included the following:L (1) The Role of Nicotinic Acetylcholine Receptors in Alcohol-Seeking Behavior, by Przemyslaw Bienkowski, MD, PhD; (2) Utilization of Linkage Analysis Combined with Microarray Technology to Identify Genes and Mechanisms Underlying Nicotine and Alcohol Use and Abuse in Humans and Rodents, by Ming D. Li, PhD; (3) Smoking and Alcoholic Chronic Pancreatitis: The Underestimated Risk?, by Roland H. Pfützer, MD; (4) Anticraving Medication in Alcohol and Nicotine Dependence, by Otto M. Lesch, MD, PhD; and (5) Pharmacotherapy for Promotion of Abstinence from Nicotine Among Alcohol-Dependent Individuals, by Bankole A. Johnson, DSc, MD, PhD. [ABSTRACT FROM AUTHOR]

This article summarizes content proceedings of a symposium held at the 2004 Research Society on Alcoholism Scientific Annual Meeting in Vancouver, Canada. The chairs were Friedrich M. Wurst and Raye Litten. The presentations were (1) Introduction, by Raye Litten; (2) Direct Ethanol Metabolites--On the Threshold From Science to Routine Use, by Friedrich M. Wurst; (3) Sialic Acid Index of Plasma Apolipoprotein J (SIJ) as a Viable Marker for Chronic Alcohol Consumption, by Philippe Marmillot; (4) The Emergence of Ethyl Glucuronide (EtG) Testing as a Tool in Monitoring Healthcare Professionals, by Gregory E. Skipper; (5) Application of Biomarkers for Alcohol Use Disorders in Clinical Practice, by Tim Neumann; (6) Utility of Biomarkers in Assessing the Efficacy of Medications for Treating Alcoholism, by Marty Javors; and (7) Discussion, by Raye Litten. [ABSTRACT FROM AUTHOR]

This article highlights the proceedings of a symposium presented at the 27th Annual Scientific Meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada, June 29, 2004. The organizers and co-chairs were Bankole A. Johnson, MD, PhD, and Robert M. Swift, MD, PhD. The presentations included (1) Introduction, by Bankole A. Johnson; (2) Safety, Tolerability, and Efficacy of gamma-Hydroxybutyric Acid and Baclofen in the Treatment of Alcohol Addiction, by Giovanni Addolorato; (3) Safety of Gabapentin in Treating Alcoholism, by Hugh Myrick; (4) New Data on the Safety and Effectiveness of Topiramate in the Treatment of Alcohol Dependence, by Bankole A. Johnson; (5) Evaluating the Risk of Benzodiazepine Prescription to Alcohol-Dependent Individuals, by Domenic A. Ciraulo; and (6) Safety and Efficacy of GABAergic Agents in Treating Alcoholics: Discussion, by Robert M. Swift. [ABSTRACT FROM AUTHOR]

The intrauterine device (IUD) is an effective contraceptive for many women. The copper-releasing IUD can be used for 10 years before replacement and is a good choice for women who cannot, or choose not to, use hormone-releasing contraceptives. However, some women experience an increase in menstrual blood loss and dysmenorrhea. The progestin-releasing IUD can be used for five years. It may reduce menorrhagia and dysmenorrhea, although some women have increased spotting and bleeding during the first months after insertion. The ideal candidates for IUD use are parous women in stable, monogamous relationships. Pregnancy, unexplained vaginal bleeding, and a lifestyle placing the woman at risk for sexually transmitted diseases are contraindications to IUD use. Insertion of the IUD can take place at any time during the menstrual cycle provided the woman is not pregnant. Before insertion, a bimanual examination and a sounding of the uterus are necessary to determine the uterus position and the depth of the uterine cavity. The IUD is inserted into the uterus according to individual protocols, with the threads cut at a length to allow the patient to check the device's position. Expulsion may occur with both types of IUDs. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing. METHODS: A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated. RESULTS: Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles. CONCLUSIONS: The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients. [ABSTRACT FROM AUTHOR]

Advances in neuroscientific knowledge have evoked interest in developing effective medications for the treatment of alcohol dependence. Pharmacological approaches that involve the use of relatively specific medications at a particular neuronal target to modulate corticomesolimbic dopamine neuronal activity, the critical pathway for expression of the reinforcing effects of abused drugs, have yielded modest efficacy in the treatment of alcohol dependence. A new approach is needed. Because corticomesolimbic dopamine neurons interact with a variety of neurotransmitters that modulate its effects in the nucleus accumbens, it might be possible to more reliably control these dopaminergic effects with a medication that acted contemporaneously on more than one neuromodulator of dopamine function. Additionally, because alcohol use results in neuronal adaptations due to sensitization, the chances of effective therapy might be bolstered by administering a medication that also has utility with mitigating its chronic effects. My proposed conceptual framework suggests that a medication that facilitates inhibitory gamma-aminobutyric acid-A input and antagonizes excitatory glutaminergic afferents to the nucleus accumbens would have pharmacotherapeutic potential in treating the alcohol dependence syndrome because these effects would act contemporaneously to suppress corticomesolimbic dopamine release. Through similar effects, topiramate might also aid chronic drinkers to wean themselves off alcohol and might ameliorate the symptoms of alcohol withdrawal. This commentary highlights the scientific concepts and clinical evidence for the development of topiramate in the treatment of alcohol dependence. Copyright 2004 Research Society on Alcoholism [ABSTRACT FROM AUTHOR]

This article represents the proceedings of a symposium at the 2003 annual meeting of the Research Society on Alcoholism in Fort Lauderdale, FL. The organizers and chairs were William J. McBride and David M. Lovinger. The presentations were (1) Mechanisms of alcohol potentiation of 5-HT3 receptor function, by David M. Lovinger and Tina Machu; (2) Chronic alcohol drinking alters 5-HT3 receptors regulating the mesolimbic dopamine system, by Richard J. Thielen; (3) 5-HT3 receptors in the VTA regulate alcohol drinking and the reinforcing effects of alcohol, by Zachary A. Rodd and James M. Murphy; and (4) Ondansetron as a treatment for 'biological' alcoholism, by John D. Roache and Bankole A. Johnson. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this paper is to present a brief review of the literature and to summarize the current status of four biochemical markers for alcohol consumption, carbohydrate deficient transferrin (CDT), total serum sialic acid (TSA), sialic acid index of apolipoprotein J (SIJ) and serum beta-hexosaminidase (beta-HEX).Findings: Of these markers, CDT has been the most widely studied, is currently thought to be the most accurate predictor of alcohol consumption, is most readily available and is the only test approved by the FDA for the identification of heavy alcohol use. TSA and SIJ have the potential to be useful markers, but have only recently been discovered, are not readily available and have not yet been studied comprehensively. Finally, the relationship between serum beta-HEX and heavy alcohol consumption has been studied for about 20 years, but the test is not readily available and has not been widely accepted or used as a marker for heavy alcohol consumption.Conclusions: These markers have the potential to be included in a combination of measurements to provide an accurate, more exact assessment of alcohol consumption in a variety of clinical and research settings. [ABSTRACT FROM AUTHOR]

BACKGROUND: Early-onset alcoholics (EOA) differ from late-onset alcoholics (LOA) by developing problem drinking during youth, experiencing severe behavioral problems, having a familial disease history, and possessing a tendency toward subsyndromal mood disturbance, including symptoms of depression, anxiety, and hostility. Subsyndromal mood disturbance is, therefore, an important component of the early-onset syndrome and may be mediated by serotonin dysfunction. Therefore, the serotonin-3 antagonist ondansetron, which has been shown to be effective at improving drinking outcomes and promoting abstinence among EOA, presumably by ameliorating serotonin dysfunction, also may exert its beneficial effects by alleviating mood disturbance among EOA. METHODS: After one lead-in week of single-blind placebo administration, subjects underwent 11 weeks of double-blind outpatient treatment using a 2 x 4 factorial design that examined age of onset (EOA versus LOA) and medication dose (placebo, or ondansetron 1, 4, or 16 microg/kg twice daily) combined with weekly standardized group cognitive-behavioral therapy. The placebo lead-in week was used to adjust for study entrance effects but not for excluding subjects. Assessments of mood were performed by using the overall score and subscales of the Profile of Mood States both at screening and at weekly intervals during the study. RESULTS: Subsyndromal mood disturbance was shown to be an important component of early-onset alcoholism. Ondansetron (16 microg/kg twice daily) showed greater therapeutic efficacy at alleviating symptoms of overall mood disturbance, fatigue, vigor, confusion/bewilderment, and depression among EOA compared with LOA. EOA-associated improvements in mood disturbance seemed to be independent of drinking behavior. CONCLUSIONS: Ondansetron has been shown to be an effective treatment for early-onset alcoholism. Ondansetron's ability to improve symptoms of depression, anxiety, and hostility among EOA may make an additional contribution to its therapeutic effect. Mechanistic studies are needed to delineate more clearly the relationship between serotonin dysfunction and pathophysiology among various subtypes of alcohol-dependent individuals. [ABSTRACT FROM AUTHOR]

The family physician often provides the first and only medical intervention for fingertip injuries. Proper diagnosis and management of fingertip injuries are vital to maintaining proper function of the hand and preventing permanent disability. A subungual hematoma is a painful condition that involves bleeding beneath the nail, usually after trauma. Treatment requires subungual decompression, which is achieved by creating small holes in the nail. A nail bed laceration is treated by removing the nail and suturing the injured nail bed. Closed fractures of the distal phalanx may require reduction but usually are minimally displaced and stable, and can be splinted. Open or intra-articular fractures of the distal phalanx may warrant referral. Patients with mallet finger cannot extend the distal interphalangeal joint because of a disruption of the extensor mechanism. Radiographs help to differentiate between tendinous and bony mallet types. Most mallet finger injuries heal with six to eight weeks of splinting, but some require referral. Flexor digitorum profundus avulsion always requires referral. Dislocations of the distal interphalangeal joint are rare and usually occur dorsally. [ABSTRACT FROM AUTHOR]

Effective treatment of acne vulgaris can prevent emotional and physical scarring. Therapy varies according to the severity of the disease. Topical medication is generally adequate in clearing comedonal acne, while inflammatory acne usually requires the addition of oral medication. Systemic antibiotics are used most frequently and can be highly effective. Newer formulations of combined oral contraceptives are also helpful in modulating sebum production in the female patient. Severe nodulocystic acne that does not respond to topical retinoids and systemic antibiotics may be treated with isotretinoin. However, the side effect profile of this medication is extensive, and physicians should be well-versed in its potential adverse effects. [ABSTRACT FROM AUTHOR]

Context: Early-onset alcoholism differs from late-onset alcoholism by its association with greater serotonergic abnormality and antisocial behaviors. Thus, individuals with early-onset alcoholism may be responsive to treatment with a selective serotonergic agent.Objective: To test the hypothesis that drinking outcomes associated with early vs late-onset alcoholism are differentially improved by the selective 5-HT(3) (serotonin) antagonist ondansetron.Design: Double-blind, randomized, placebo-controlled clinical trial.Settings: University of Texas Health Science Center in Houston (April 1995-June 1998) and University of Texas Health Science Center in San Antonio (July 1998-December 1999).Participants: A total of 321 patients with diagnosed alcoholism (mean age, 40.6 years; 70.5% male; 78.6% white) were enrolled, 271 of whom proceeded to randomization.Interventions: After 1 lead-in week of single-blind placebo, patients were randomly assigned to receive 11 weeks of treatment with ondansetron, 1 microg/kg (n = 67), 4 microg/kg (n = 77), or 16 microg/kg (n = 71) twice per day; or identical placebo (n = 56). All patients also participated in weekly standardized group cognitive behavioral therapy.Main Outcome Measures: Self-reported alcohol consumption (drinks per day, drinks per drinking day, percentage of days abstinent, and total days abstinent per study week); and plasma carbohydrate deficient transferrin (CDT) level, an objective and sensitive marker of transient alcohol consumption.Results: Patients with early-onset alcoholism who received ondansetron (1, 4, and 16 microg/kg twice per day) compared with those who were administered placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P =.03, P =.01, and P =.02, respectively) and drinks per drinking day (4.75, 4.28, and 5.18 vs 6.90; P =.03, P =.004, and P =.03, respectively). Ondansetron, 4 microg/kg twice per day, was superior to placebo in increasing percentage of days abstinent (70.10 vs 50.20; P =.02) and total days abstinent per study week (6.74 vs 5.92; P =.03). Among patients with early-onset alcoholism, there was a significant difference in the mean log CDT ratio between those who received ondansetron (1 and 4 microg/kg twice per day) compared with those who received the placebo (-0.17 and -0.19 vs 0.12; P =.03 and P =.01, respectively).Conclusion: Our results suggest that ondansetron (particularly the 4 microg/kg twice per day dosage) is an effective treatment for patients with early-onset alcoholism, presumably by ameliorating an underlying serotonergic abnormality. JAMA. 2000;284:963-971 [ABSTRACT FROM AUTHOR]

Seborrheic dermatitis is a chronic inflammatory disorder affecting areas of the head and trunk where sebaceous glands are most prominent. Lipophilic yeasts of the Malassezia genus, as well as genetic, environmental and general health factors, contribute to this disorder. Scalp seborrhea varies from mild dandruff to dense, diffuse, adherent scale. Facial and trunk seborrhea is characterized by powdery or greasy scale in skin folds and along hair margins. Treatment options include application of selenium sulfide, pyrithione zinc or ketoconazole-containing shampoos, topical ketoconazole cream or terbinafine solution, topical sodium sulfacetamide and topical corticosteroids. [ABSTRACT FROM AUTHOR]

Icebergs represent hazards to ships and maritime activities and therefore their detection is essential. Synthetic Aperture Radar (SAR) satellites are very useful for this, due to their capability to acquire data under cloud cover and during day and night passes. In this work, we compared six state-of-the-art polarimetric target detectors to test their performance and ability to detect small-sized icebergs HH and HV. We also compared these detectors with single-polarimetric intensity channels and we tested using two scenarios: open ocean and sea ice. Our results show that the multi-look polarimetric whitening filter (MPWF) and the optimal polarimetric detector (OPD) provide the most optimal performance in quad- and dual-polarimetric mode detection. The analysis shows that, overall, quad-polarimetric detectors provide the best detection performance. When the false alarm rate (PF) is fixed to 10−5, the probabilities of detection (PD) are 0.99 in open ocean and 0.90 in sea ice. Dual-polarimetric or single-polarimetric detectors show an overall reduction in performance (the ROC curves show a decrease), but this degradation is not very large (120 m, as they are easier to detect). However, the differences between quad- and dual- or single-polarimetric detectors became much more evident when the PF value was fixed to low detection probabilities 10−6 (i.e., smaller icebergs). In the single-polarimetric mode, the HV channel showed PD values of 0.62 for open ocean and 0.26 for sea ice, compared to values of 0.81 (open ocean) and 0.77 (sea ice) obtained with quad-polarimetric detectors.

Advances in neurobiology support the development of medications to treat alcoholism by modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain. Among the most promising new medications is acamprosate, which appears to decrease the intensity of craving after a person has stopped drinking. Naltrexone (ReVia) has been shown to decrease alcohol consumption, although its practical effectiveness may be compromised by poor patient compliance and other factors. Ondansetron shows promise for decreasing drinking and increasing abstinence rates among early onset alcoholics, who respond poorly to psychosocial treatment alone. Researchers are investigating whether the use of specific medications in combination can further enhance their effectiveness. Additional research is needed to determine how medications interact with different psychosocial factors and treatments. [ABSTRACT FROM AUTHOR]

Flexible sigmoidoscopy is an important screening procedure because of its ability to detect early changes in the distal colon. The 60-cm flexible sigmoidoscope provides excellent visualization with minimal discomfort to patients. Successful sigmoidoscopy requires adequate patient preparation, proper equipment and an experienced examiner who can recognize both normal and abnormal findings. Complications arising from sigmoidoscopy are rare, but patients may experience some cramping, gas or watery stools. Screening and primary preventive measures, including regular exercise and increased dietary fiber intake, can lower the morbidity and mortality associated with colorectal cancer. [ABSTRACT FROM AUTHOR]

Icebergs are ocean hazards which require extensive monitoring. Synthetic Aperture Radar (SAR) satellites can help with this, however, SAR backscattering is strongly influenced by the properties of icebergs, together with meteorological and environmental conditions. In this work, we used five images of quad-pol ALOS-2/PALSAR-2 SAR data to analyse 1332 icebergs in five locations in west and east Greenland. We investigate the backscatter and polarimetric behaviour, by using several observables and decompositions such as the Cloude–Pottier eigenvalue/eigenvector and Yamaguchi model-based decompositions. Our results show that those icebergs can contain a variety of scattering mechanisms at L-band. However, the most common scattering mechanism for icebergs is surface scattering, with the second most dominant volume scattering (or more generally, clouds of dipoles). In some cases, we observed a double bounce dominance, but this is not as common. Interestingly, we identified that different locations (e.g., glaciers) produce icebergs with different polarimetric characteristics. We also performed a multi-scale analysis using boxcar 5 × 5 and 11 × 11 window sizes and this revealed that depending on locations (and therefore, characteristics) icebergs can be a collection of strong scatterers that are packed in a denser or less dense way. This gives hope for using quad-pol polarimetry to provide some iceberg classifications in the future.