JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Chronic Obstructive Pulmonary Disease hospitalization rates in Massachusetts: a trend analysis.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) causes a huge economic burden and >80% of COPD cases are attributable to smoking. Massachusetts introduced a comprehensive Tobacco Control Program (MTCP) in January 1993. A trend analysis of COPD hospitalization rates might indirectly reflect the potential impact of such comprehensive tobacco control programs. METHODS: Age-adjusted COPD hospitalization rates/100,000 was abstracted from the Massachusetts Community Health Information Profile Database between 1989 and 2005. Joinpoint Regression Analyses program was employed to estimate annual percent changes (APC) in COPD rates by age, sex and race. RESULTS: In 1989, 265/100,000 age-adjusted COPD hospitalization rates were reported that increased to 423/100,000 in 1993, and then declined to 329/100,000 in 2005. A significant annual decline of 5.6 percentage points was observed in overall COPD rates from 1993 onwards. A similar temporal pattern, with an age-gradient and a slower annual decline in female COPD rates relative to male COPD rates, was observed. COPD rates in both Blacks and Whites were similar to the general overall pattern. Such consistent annual declines in COPD hospitalization rates from 1993 onwards in Massachusetts also closely correspond to the introduction of the MTCP in January 1993. CONCLUSION: The findings indirectly suggest that smoking cessation should remain the cornerstone strategy for the prevention and control of COPD burden. However, additional studies across different population settings are essential for a definitive conclusion with regard to the immediate impact of a comprehensive tobacco control program on COPD hospitalization rates showing possible gender susceptibility.

Secular trends in adult male smoking from 1992 to 2006 in South Korea: age-specific changes with evolving tobacco-control policies.

OBJECTIVES: For years, South Korea has had one of the highest levels of tobacco use among males in the world, but a steady decline has been observed recently. This study examined how the smoking behaviour of male adults changed with age after the implementation of national tobacco control policies in 1995. STUDY DESIGN: Repeated cross-sectional study using a national survey. METHODS: Data were obtained from the 1992, 1995, 1999, 2003 and 2006 results of a repeated cross-sectional survey, the Social Statistics Survey. The smoking status of adult men was compared before (1992 and 1995 surveys) and after (1999, 2003 and 2006 surveys) the implementation of government-directed tobacco control policies using graphical methods and logistic regression analysis. RESULTS: After the implementation of tobacco control policies, the percentage of current male smokers decreased while the percentage of former smokers increased markedly. Smoking prevalence among older men (aged 50 years or more) reduced initially, and this decline was more pronounced after the tobacco control policies were implemented. Smoking prevalence in younger men (aged 30-49 years) declined in 2003 when more comprehensive tobacco control policies were implemented. CONCLUSIONS: This study suggests that comprehensive tobacco control policies in South Korea reduced smoking prevalence among males, initially among older men and later among both older men and younger men.

FcgammaRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients.

The aim of this study was to determine the distribution of the FcgammaRlla and FcgammaRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgammaRlla 131 R/H and FcgammaRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgammaRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgammaRIIa genotypes between the SLE and the controls (P=0.002 for R/R131 vs R/H131 and H/H131, OR 2.5 (95% Cl 1.4-4.5), but not in FcgammaRIIIa genotypes. FcgammaRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% Cl 1.03-1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgammaRlla-R/R131 and in FcgammaRIIa-R allele. In 300 SLE patients, high binding allele combination H131/V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131/F176 allele combination among four FcgammaRIIa/FcgammaRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgammaRIIa-R/R131 or R131-allele than male controls, but FcgammaRIIa or FcgammaRIIIa genotypes had no association with renal involvement in male SLE patients. FcgammaRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anticardiolipin antibody (+) and anti-Ro antibody (+) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgammaRIIa or FcgammaRIIIa genotypes between female SLE and female controls, but FcgammaRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgammaRIIa R/R131 among three FcgammaRIIa genotypes, and serositis in FcgammaRIIIa-F/F176 among three FcgammaRIIIa genotypes. FcgammaRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgammaRIIa-RI31 homozygote and R131 allele were a predisposing factor, and H131/V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgammaRIIa and FcgammaRIIIa showed somewhat different clinical associations between the genders.

Reliability and validity of systemic lupus activity measure-revised (SLAM-R) for measuring clinical disease activity in systemic lupus erythematosus.

New clinical scales for semiquantitating disease activity in systemic lupus erythematosus (SLE) are widely used in research. They are reliable and valid measures. One of the original scales, the Systemic Lupus Activity Measure (SLAM), has been modified based on experience with it in multi-observer studies and training of individuals in its use. We tested the psychometric properties of the revised SLAM (SLAM-R). SLAM-R was tested on 30 SLE patients, who fulfilled 1997 revised ACR criteria and were selected to represent a range of disease activity. The patients were evaluated independently by two physicians, who studied the instruction booklet and who had never used SLAM-R, on two occasions 2-4 weeks apart. At the first visit, the physician's global assessment of activity using visual analog scale, anti-dsDNA Ab, C3 and C4 were checked for construct validity. The psychometric properties were analyzed with nested analysis of variance and Pearson's correlation coefficient using SAS. All patients were female, the median age was 31 (15-52) y, and the mean score of SLAM-R was 10.5 +/- 5.3 (3-26). Estimates of reliability were 0.78 of inter-rater, 0.61 of inter-visit, 0.76 of physician 1 between visits, and 0.56 of physician 2 between visits. Among subcategories except 'Eye,' the 'Gastrointestinal' category had the highest (0.96) and the 'Neuromotor' category had the lowest inter-rater reliability (0.50). With respect to construct validity, the correlation of SLAM-R scores with the disease activity variables except C4 was high and statistically significant. In conclusion, the SLAM-R is reliable and valid for measuring clinical disease activity in SLE.

Sun protection practices in preadolescents and adolescents: a school-based survey of almost 25,000 Connecticut schoolchildren.

Sun protection practices in children and adolescents fall well below national recommendations. We present the results of a survey of sun protection use and other health-related behaviors in a sample of Connecticut Caucasian students aged 9 through 18 years (N = 24,645). Our objectives were to estimate the prevalence of sun protection use and to evaluate the relationship between sun protection use and health-risk behaviors and attitudes about appearance. We present data from 1988 through 1995 from the Connecticut Health Check, a health risk appraisal survey sponsored by the Connecticut Department of Public Health. Students enrolled in public and private elementary junior as well as senior high schools took the self-administered anonymous survey, which included multiple-choice questions about use of sun protection, cigarettes, and alcohol and about body image and self-esteem. We report prevalence proportions for use of sun protection by demographic features. We compared the proportion of students in 3 categories of outcome (always, sometimes, and never use sun protection) who reported various health-risk behaviors. Twenty percent of the sample reported always using sun protection; this is well below national goals set forth in the Healthy People 2000 recommendations. Sun protection use was inversely related to age and was higher among girls than boys at all ages. At all ages, students who did not use sun protection were more likely than those who did to report other health risk behaviors, such as use of cigarettes and alcohol. The data suggested that use of sun protection is associated with positive attitudes about appearance and self-image. Use of sun protection may be one component of an overall mode of health awareness and behavior. Programs promoting safe sun practices should target boys and be integrated into an overall campaign aimed at other risk-taking behaviors.

A public health response to emerging technology: expansion of the Massachusetts newborn screening program.

The development of a new technology, called tandem mass spectrometry (tandem MS), has challenged governments worldwide to consider expanding universal newborn screening for rare metabolic disorders. In 1997 the Massachusetts Department of Public Health developed a public process to meet this challenge. After addressing significant medical, legal, ethical, and logistical issues raised by tandem MS, Massachusetts incorporated one new disorder into the mandatory newborn screen and developed an optional pilot program for 20 additional disorders. The Massachusetts experience has wide relevance for other nations and states. As screening protocols are contemplated for entire populations-for newborns and others- it will remain essential that the public participate in an open process of reviewing the justification for and logistics of screening.

Cancer skills laboratories for medical students: a promising approach for cancer education.

BACKGROUND: Most medical students graduate without the skills necessary to assist patients in cancer control. To address this problem, the authors developed a cancer skills laboratory for second-year medical students. METHODS: The skills laboratory consists of two hours of training, with 15 minutes allotted per station (six to eight students assigned per station). Faculty and fellows lead the stations on prostate cancer, breast cancer, colorectal cancer, skin cancer, counseling for smoking cessation, and a discussion of anti-tobacco advertisements. Students completed pre- and post-laboratory surveys consisting of ten brief questions. RESULTS: Overall, 94% of eligible students in 1997 and 1998 completed the surveys. Using a five-point scale, self-rated skill level increased from 2.12 to 3.83 when all modalities were averaged (p < .001). CONCLUSIONS: Cancer skills laboratories are a promising new means for cancer education.

Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone in patients with refractory cutaneous T-cell lymphoma.

BACKGROUND: This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). METHODS: Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. RESULTS: After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. CONCLUSIONS: EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.

Screening for malignant melanoma: A cost-effectiveness analysis.

BACKGROUND: Skin cancer is the most common cancer in the United States. Increasing evidence suggests that screening for malignant melanoma is effective, but its cost-effectiveness has not been determined. OBJECTIVE: We attempted to determine the effectiveness and costs of a visual screen to diagnose malignant melanoma in high-risk persons. METHODS: We developed a decision analysis comparing no skin cancer screen with a single screen by a dermatologist. Clinical outcomes included malignant melanoma, nonmelanoma skin cancer, or no skin cancer. Life expectancy and costs of care were projected on the basis of clinical findings. RESULTS: Skin cancer screening increased average discounted life expectancy from 15.0963 years to 15.0975 years. Based on the prevalence of malignant melanoma, however, this translates into an increased discounted life expectancy of 0.9231 years for each person with diagnosed melanoma. Using a cost of $30 per screen, total skin cancer-related costs for a cohort of 1 million people increased from $826 million with no screen to $861 million with screening, with an increase of 1200 years of life. This results in an incremental cost-effectiveness ratio of $29,170 per year of life saved (YLS) with screening. Sensitivity analysis showed that the cost-effectiveness ratio for screening remained below $50,000/YLS if the prevalence of melanoma in the screened population was at least 0. 0009, the probability that a melanoma detected in screening was localized was at least 94.8%, or the cost of each screen was below $57. CONCLUSION: Skin cancer screening in high-risk patients is likely to be associated with a small increase in discounted life expectancy and is reasonably cost-effective compared with other cancer screening strategies.

Medical students' knowledge, attitudes, skills, and practices of cancer prevention and detection.

BACKGROUND: Surveys of U.S. physicians show deficiencies in cancer detection and counseling skills. Thus, there is a compelling need to provide skills teaching during medical school for cancers with preventable mortality and for counseling techniques for smoking prevention and cessation. METHODS: In advance of the integration of initiatives for cancer education into the medical school curriculum, the authors conducted a baseline survey of students' knowledge, attitudes, skills, practices, observation, and training (KASPOT) related to cancer education. Eighty-one percent of Boston University School of Medicine students (n = 499) completed surveys. RESULTS: The students reported higher levels of KASPOT for breast and cervical cancers, compared with skin cancer examination or tobacco use cessation or prevention counseling. More than half of third- and fourth-year students reported that too little emphasis was given to cancer control education. CONCLUSIONS: It appears that students' practice and skills for detection of the most common cancer (skin cancer), and for cancers with the greatest mortality (tobacco-related cancers) are deficient. Revisions in medical students' curricula should seek to address these shortcomings.

Public knowledge, awareness, and perceptions of the association between skin aging and smoking.

BACKGROUND: Although the tobacco industry promotes images of glamour, 2 decades of epidemiologic research have concluded the opposite: smokers have enhanced facial aging and skin wrinkling compared with nonsmokers. OBJECTIVE: The purpose of this study was to obtain information on the public's awareness of the association between cigarette smoking and skin aging. METHODS: In the spring of 1994, the Maine-wide Cooperative Telephone Survey conducted telephone interviews in 678 randomly selected, nonseasonal dwelling units in Maine. From each dwelling unit, one randomly selected adult resident was interviewed to assess awareness of the association of skin aging with smoking. RESULTS: Fifty-eight percent of those persons interviewed had smoked at least 100 cigarettes, and among them, 24% were current smokers (28% men, 21% women). After adjusting for sex, age, and education, current smokers remained less likely to be aware of this association compared with former (prevalence ratio, 0.78; 95% confidence interval, 0.64-0.95) and never smokers (prevalence ratio, 0.87; 95% confidence interval, 0.70-1.07). However, nearly one fourth of smokers in this study believed that most or some smokers would consider this information in their decision to quit, with slightly higher findings in young smokers. CONCLUSION: These findings are of public health importance. While strategies for framing messages about the association between smoking and facial aging await further study, this association deserves to be considered in all tobacco control and counter-advertising campaigns.

The New Moms Project: educating mothers about sun protection in newborn nurseries.

Sun protection habits should begin early in life and be taught as part of routine preventive health care. Early teaching of parents aims to introduce an easily achieved means of sun protection with the goal of instilling these practices as habits in the parents and their young children. We developed a maternity nurse-led intervention for 187 mothers at newborn nurseries in Falmouth, Massachusetts, combining educational material and personal discussions. One year after the intervention we successfully contacted 73% of the mothers. Nearly 90% recalled the informational program and equal numbers stated that receiving educational materials in the newborn nursery was timely. Nearly two-thirds of mothers reported that this was the only sun protection information received from a provider in the past year.

The Falmouth Safe Skin Project: evaluation of a community program to promote sun protection in youth.

A multidimensional community-based skin cancer prevention program was conducted in Falmouth, Massachusetts, combining community activism with publicity campaigns and behavioral interventions to improve sun protection knowledge; attitudes; and practices in parents, caregivers, and children. The program was associated with improvements in target outcomes, based on two telephone surveys of random samples of parents (n = 401, 404). After program implementation, fewer parents reported sunburning of their children, particularly among children 6 years old or younger (18.6% in 1994 vs. 3.2% in 1997), and more parents reported children using sunscreen, particularly continuous use at the beach (from 47.4% to 69.9% in younger children). Hat and shirt use did not increase. Improvements also were seen in parent role modeling of sun protection practices, parents' self-efficacy in protecting children from the sun, and sun protection knowledge. While these findings must be interpreted cautiously, they do suggest that this project was effective in promoting sun protection.

Participant satisfaction and value in American Academy of Dermatology and American Cancer Society skin cancer screening programs in Massachusetts.

BACKGROUND: More than 1 million Americans have attended the American Academy of Dermatology's Melanoma/Skin Cancer Screening Programs since 1985. However, there have been no reports of the participants' perceived value, satisfaction, and benefits of skin cancer screening. OBJECTIVE: We attempted to measure the benefits and subsequent screening practices of persons with presumptive positive screening diagnoses. METHODS: A self-administered questionnaire was sent to participants with positive screening diagnoses in Massachusetts. RESULTS: Of the 643 respondents, 81% rated their satisfaction as high and 84% had similar ratings for the value of the screening. Screenings apparently led to an increase in self-screening (60% before screening compared with 84% after screening). CONCLUSION: Although screening appears to have relatively strong benefits, further studies should be conducted nationally.

Genetically engineered transgenic plants with the domain 1 sequence of tobacco mosaic virus 126 kDa protein gene are completely resistant to viral infection.

In many plant RNA viruses, Domains 1, 2 and 3 are conserved in replicase proteins. In order to examine the interference of viral replication by the Domain 1 sequence, we generated transgenic plants transformed with DNA corresponding to the Domain 1 sequence of the TMV 126 kDa protein. This DNA sequence includes the TMV RNA from nucleotides 1 to 2,149, which comprises both the 5'-untranslated and methyl transferase region. The transgenic plants obtained showed complete resistance to TMV infection. The presence of the Domain 1 sequence in the plants completely prevented local necrosis in Nicotiana tabacum cv. Xanthi nc, and any systemic development of symptoms in Nicotiana tabacum Xanthi upon TMV inoculation. Most transgenic plants sustained the conferred resistance even under TMV inoculum concentrations up to as high as 1,000 microg/ml. To detect any accumulation of TMV coat protein or viral RNA in infected transgenic plants, immunochemical tests and Northern blot analyses were carried out. Neither viral RNA or coat protein was detectable in the systemic leaves of the completely resistant transgenic plants, whereas they were accumulated in large quantities in all of the control plants. Because of the conservation of Domain 1 in many plant RNA viruses, the acquisition of resistance to virus infection using the Domain 1 sequence appears to be a very effective strategy for breeding of viral resistant plants.

Multiple cerebellar infarction due to vertebral artery obstruction and bulbar symptoms associated with vertical subluxation and atlanto-occipital subluxation in ankylosing spondylitis.

Ankylosing spondylitis (AS) results in disease-specific inflammation at the site of ligamentous insertion into the bone. Atlantoaxial joint subluxation and vertical subluxation of the axis may occur as a consequence of instability resulting from the inflammatory process. Spontaneous anterior atlantoaxial subluxation is a well recognized complication in about 2% of patients with AS, and presents with or without signs of spinal cord compression. Vertical subluxation may follow anterior or posterior subluxation. It was noted in 3-8% of patients with rheumatoid arthritis, but is an exceedingly rare complication of AS. Moreover, it has never been reported that multiple cerebellar infarction and bulbar symptoms developed spontaneously due to atlanto-occipital subluxation and vertical subluxation in a patient with a long [corrected] history of AS. We describe a man with AS who developed multiple cerebellar infarction due to vertebral artery obstruction and bulbar symptoms associated with atlanto-occipital subluxation and vertical subluxation.