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To evaluate the efficacy of adjuvant chemoradiation therapy (CRT) for pancreatic adenocarcinoma patients ≥ 75 years of age.The study group of 655 patients underwent pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma at the Johns Hopkins Hospital over a 12-year period (8/30/1993 to 2/28/2005). Demographic characteristics, comorbidities, intraoperative data, pathology data, and patient outcomes were collected and analyzed by adjuvant treatment status and age ≥ 75 years. Cox proportional hazards analysis determined clinical predictors of mortality and morbidity.We identified 166 of 655 (25.3%) patients were ≥ 75 years of age and 489 of 655 patients (74.7%) were75 years of age. Forty-nine patients in the elderly group (29.5%) received adjuvant CRT. For elderly patients, node-positive metastases (p = 0.008), poor/anaplastic differentiation (p = 0.012), and undergoing a total pancreatectomy (p = 0.010) predicted poor survival. The 2-year survival for elderly patients receiving adjuvant therapy was improved compared with surgery alone (49.0% vs. 31.6%, p = 0.013); however, 5-year survival was similar (11.7% vs. 19.8%, respectively, p = 0.310). After adjusting for major confounders, adjuvant therapy in elderly patients had a protective effect with respect to 2-year survival (relative risk [RR] 0.58, p = 0.044), but not 5-year survival (RR 0.80, p = 0.258). Among the nonelderly, CRT was significantly associated with 2-year survival (RR 0.60, p0.001) and 5-year survival (RR 0.69, p0.001), after adjusting for confounders.Adjuvant therapy after PD is significantly associated with increased 2-year but not 5-year survival in elderly patients. Additional studies are needed to select which elderly patients are likely to benefit from adjuvant CRT.

This article is a criticism of the "Paradigm Shift in No-Fault 'Serious Injury' Litigation" by Joseph D. Nohavicka which concluded that the lower courts of New York were charged with removing fraudulent serious injury cases from the court system pursuant to the Court of Appeal’s Decision in Pommells v. Perez, 4 N.Y.3d 566 (2005). His article argues that the Pommells decision elaborates longstanding guidelines mandated by the Court of Appeals, clarifying the burdens on a plaintiff seeking to defeat summary judgment where there is a gap or cessation of treatment or sufficient proof in support of the motion establishing a pre-existing condition as the cause of plaintiff’s injuries. No duty is placed on trial courts to determine fraud in the summary judgment context.

Interaction of the ends of the exons with loop 1 of the U5 snRNA aligns the exons for ligation in the second step of pre-mRNA splicing. To study the effect of Prp18 on the exons’ interactions, we analyzed the splicing of pre-mRNAs with random sequences in the exon bases at the splice junctions. The exon mutations had large effects on splicing in yeast with a Prp18 protein lacking its most conserved region, but not in wild-type yeast. Analysis of splicing kinetics demonstrated that only the second step was affected in vivo and in vitro, showing that Prp18—and specifically its conserved region—plays a key role in stabilizing the interaction of the exons with the spliceosome at the time of exon joining. Superior exon sequences defined by the prp18 results accelerated the second step of splicing by wild-type spliceosomes with inefficient AT-AC pre-mRNAs, implying that normal exon interactions follow the rules we discerned for prp18 splicing. Our results show that As are preferred at the ends of both exons and support a revised model of the interactions of the exons with U5 in which the exons are arranged in a continuous double helix that facilitates the second reaction.

Background Low-density lipoprotein (LDL)–based guidelines are currently used to initiate and monitor cholesterol-lowering therapy. Methods Using stratified analyses, data from the Framingham Heart Study and the Coronary Primary Prevention Trial were evaluated to determine whether (1) cholesterol levels (total cholesterol [TC] or LDL [low-density lipoprotein]) better discriminated risk for coronary heart disease (CHD) than cholesterol ratios (LDL/HDL [high-density lipoprotein] or TC/HDL); and (2) whether changes in ratios better predicted risk reduction than changes in levels. Results Individuals with similar LDL/HDL ratios had similar risks for CHD regardless of whether they had high LDL levels or low LDL levels (23% vs 23% for the CPPT, 13.8% vs 14% for FHS men, and 8.6% vs 10.9% for FHS women). Among men with similar initial LDL/HDL ratios and similar changes in LDL/HDL ratios, risks for CHD did not differ (20.3% compared with 21.0%; p =0.96) between those with the largest and smallest reductions in LDL levels (21.3% compared with 6.5%). Among men with similar initial LDL levels and similar LDL reductions, a 20% reduction in risk for CHD was seen (19.5% compared with 24.5%; p =0.005) between those with the largest and smallest reductions in LDL/HDL ratios (23% compared with 4.6%). TC/HDL had predictive ability similar to LDL/HDL. Conclusions Cholesterol levels do not provide incremental predictive value over cholesterol ratios in identifying people at risk for CHD. Changes in ratios are better predictors of successful CHD risk reduction than changes in levels. Future guidelines should consider incorporating ratios in initiating and monitoring successful lipid-lowering therapy.

for non-small-cell lung cancer (NSCLC) Eric Xanthopoulos,*Ŧ MD, JD, Michael Corradetti,*Ŧ MD, PhD, Simon Cheng,** MD, PhD, David Horowitz,** MD, PhD, Annemarie Fernandes, MD,* Amanda Lusa,** MD, KS Clifford Chao,** MD, Ramesh Rengan,* MD, PhD * Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania ** Columbia University, New York New York ( Ŧco-first author; abstract #3014; please direct questions to: Eric Xanthopoulos, MD, JD at eric.xanthopoulos@uphs.upenn.edu) PURPOSE: Prophylactic cranial irradiation (PCI) may delay the incidence of brain metastases in non-smallcell lung cancer patients after primary therapy, but its impact on survival is uncertain. We report on the largest and longest study of survival in patients treated with or without prophylactic cranial irradiation for non-small-cell lung cancer.

Among patients with locally advanced disease, no standard exists for treatment. Initial reports of neoadjuvant chemotherapy with gemcitabine, docetaxel and capecitabine (GTX) with or without additional neoadjuvant chemoradiation showed favorable rates of conversion to resectability with negative margins. 2-3 This study investigated the safety and tolerability to neoadjuvant GTX chemotherapy followed by combined radiotherapy and chemotherapy (gemcitabine and capecitabine) in patients with borderline resectable pancreatic cancer.

Poor reimbursement of pediatricians for behavioral and developmental services and the disarray of children’s mental health services in the state led leaders of the North Carolina chapter of the American Academy of Pediatrics to organize an advocacy effort with the following objectives: 1) to articulate pediatricians’ perspective on the current crisis in delivering and coordinating children’s behavioral health services; 2) to represent the collective voice of both academic and community pediatricians in dialogue with mental health providers, Medicaid leaders, and the health and mental health segments of state government; 3) to build consensus about an achievable plan of action to address pediatricians’ reimbursement and systems issues; 4) to develop a full and appropriate role for pediatricians as providers and, potentially, coordinators of behavioral health care; and 5) to facilitate implementation of Medicaid changes, as a first step in carrying out this plan. This article describes the 24-month process that achieved these objectives.

We report that the cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the cyclophilin is exposed. The cyclophilin inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins.

Purpose/Objective(s): Locally advanced non-small cell lung carcinoma remains a therapeutic challenge for clinicians. Currently the standard of care is multimodality therapy, but sequencing of multimodality therapy is unclear. Population based studies suggest that neoadjuvant radiation (N-RT) offers an overall and cause-specific survival benefit over adjuvant radiation (A-RT) in the treatment of Stage III NSCLC. The goal of this study was to identify the factors which affect the survival benefit of neoadjuvant radiation in Stage III NSCLC.

Historians acknowledge this author's Boston Against Busing: Race, Class, and Ethnicity in the 1960s and 1970s[1991] as a path‐breaking profile of a movement combining reformist, egalitarian, and an...

The splicing factor Prp18 is required for the second step of pre-mRNA splicing. We have isolated and determined the crystal structure of a large fragment of the Saccharomyces cerevisiae Prp18 that lacks the N-terminal 79 amino acids. This fragment, called Prp18Δ79, is fully active in yeast splicing in vitro and includes the sequences of Prp18 that have been evolutionarily conserved. The core structure of Prp18Δ79 is compact and globular, consisting of five α-helices that adopt a novel fold that we have designated the five-helix X-bundle. The structure suggests that one face of Prp18 interacts with the splicing factor Slu7, whereas the more evolutionarily conserved amino acids in Prp18 form the opposite face. The most highly conserved region of Prp18, a nearly invariant stretch of 19 aa, forms part of a loop between two α-helices and may interact with the U5 small nuclear ribonucleoprotein particles. The structure is consistent with a model in which Prp18 forms a bridge between Slu7 and the U5 small nuclear ribonucleoprotein particles.

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.

e17562 Background: Treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) is associated with high rates of local control and long-term overall survival. With increasing frequency, SBRT is a treatment option for operable tumors which raises the question of the risk of long-term toxicities such as radiation-induced secondary malignancies. There has been no previous risk assessment or epidemiological studies of secondary malignancies with high-dose hypofractionated SBRT. In this study, we seek to quantify the predicted rates of secondary lung malignancies in patients treated with SBRT for stage I-II NSCLC. Methods: Treatment plans for 14 stage I-II NSCLC patients treated with definitive-intent SBRT at Columbia University Medical Center were retrospectively assessed. Median patient age was 73 years (range 54 - 86) with median tumor size of 2.8 cm (range 1.2 - 5.0). SBRT doses ranged from 40-60 Gy in 3-5 fractions. Dose-volume histograms for target PTV and normal lung were generated from planning CT scans. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk and the median lifetime estimated relative risk of secondary lung malignancies for each plan. These risks were then compared using 2-sided t-tests. Results: For all patients, the median lifetime estimated absolute risk of secondary lung malignancy was 1.06% (95% CI 0.62%-1.98%), and the median lifetime estimated relative risk of secondary lung malignancy was 1.61 (95% CI 1.47-1.75) after SBRT. For patients aged less than 65 years, median estimated absolute risk of secondary malignancies was higher (2.8%) than for patients age 65 and older (0.37%), p < 0.001. PTV volume less than 50 cc vs greater than 50 cc, T1 vs T2 tumors, and gender were not significantly associated with differences in estimated absolute risk or estimated relative risk of secondary malignancies. Conclusions: As SBRT is potentially indicated in younger medically operable patients, the long-term late toxicities need to be determined. This study suggests that the risk of second lung malignancies from high-dose SBRT even in younger patients would be minimal.

e15162 Background: The risk of secondary rectal malignancies (SRMs) is a significant concern following radiation therapy for prostate cancer patients. Modern prostate radiotherapy techniques include the use of intensity modulated radiation therapy (IMRT) and rectal balloons to decrease treatment related toxicity. These technologies may also lower the likelihood of radiation-induced SRMs. In this study, a novel biologically-based carcinogenesis model was used to quantify and to compare the predicted risks of SRMs in men treated with or without a rectal balloon in place using either standard 3-D conformal radiotherapy (3D-CRT) or IMRT radiotherapy. Methods: Treatment plans were developed for ten clinically localized prostate cancer patients using CT scans obtained both with and without a rectal balloon in place. Target and normal structures were contoured, and dose-volume histograms (DVHs) for these organs were determined with a planned 3D-CRT dose of 75.6 Gy or with a planned IMRT dose of 81 Gy. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk of SRMs for each plan. These risks were then compared to one another and to the baseline population. Results: Treatment with IMRT and a rectal balloon in place resulted in a significantly lower mean rectal wall dose in all patients compared with treatment with 3D-CRT without a rectal balloon. The average mean rectal wall dose with IMRT and a rectal balloon in place was 31.0 Gy versus 40.1 Gy with 3D-CRT without the rectal balloon (p < 0.001). A significantly higher risk of SRMs was predicted for patients treated with 3-D CRT without rectal balloons when compared with patients treated with IMRT with balloons in place (p < 0.001, relative risk 1.30; 95% confidence interval 1.16-1.44). Conclusions: For prostate cancer patients treated with definitive radiotherapy, the use of IMRT and rectal balloons during radiation, when compared to treatment with 3-D conformal radiotherapy, is associated with a significant reduction in the predicted risk of secondary rectal malignancies.

7050 Background: Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases in NSCLC patients after primary therapy, but its impact on survival is uncertain. We report on the largest study of survival in patients treated with and without PCI for non-small cell lung cancer (NSCLC). Methods: We reviewed 17 Surveillance, Epidemiology and End Results (SEER) registries for a retrospective study on patients who had PCI as part of their primary treatment for NSCLC from 1988 - 97. Cases were limited to those with non-metastatic (Stage I-III) NSCLC. To balance the cohorts, we matched each PCI patient with four non-PCI patients on stage, histology, race and sex. Associations between treatment type, clinical factors, and demographics were assessed using the Chi-squared test. Survival time was calculated as the number of months from diagnosis to the date of death. Survival was censored as of the last month when patients were known to be alive. Overall (OS) and cancer cause-specific survival (CSS) were investigated using the Kaplan-Meier, competing risks, Cox proportional hazards, and log-rank tests. Results: We found 472 PCI matched to 1,888 non-PCI patients. Characteristics were balanced across groups: race (p = 1.00), sex (p = 0.95), histology (p = 1.00), stage (p = 1.00), and surgery (p = 0.81). PCI group was younger, median age 64 vs 68 (p < 0.01). PCI vs no PCI median OS was 8 vs 10 months (p < 0.01). OS was 14% vs 28% at 2 years and 5% vs 12% at 5 years, PCI vs no PCI respectively (p < 0.01). Stage III OS was also different; 10% vs 21% at 2 years, PCI vs no PCI respectively (p < 0.01). Median CSS was the same at 9 months in both groups. Median follow-up was 14 years. Conclusions: PCI was not associated with improved OS or CSS in these NSCLC patients, and PCI may have a detrimental effect on OS. In limited-stage small cell lung cancer, a retrospective SEER analysis during the 1988 – 97 period showed a survival benefit in treated patients with PCI, which has been confirmed with prospective studies. To date, 4 prospective trials examining PCI for NSCLC have shown a reduced incidence of brain metastases, but the effect on survival is unclear. Further investigation is needed to determine whether PCI for NSCLC increases the risk of other causes of death.

While searching for a human homolog of the S.cerevisiae splicing factor PRP18, we found a polypeptide that reacted strongly with antibodies against PRP18. We purified this polypeptide from HeLa cells using a Western blot assay, and named it p54nrb (for nuclear RNA-binding protein, 54 kDa). cDNAs encoding p54nrb were cloned with probes derived from partial sequence of the purified protein. These cDNAs have identical coding sequences but differ as a result of alternative splicing in the 5' untranslated region. The cDNAs encode a 471 aa polypeptide that contains two RNA recognition motifs (RRMs). Human p54nrb has no homology to yeast PRP18, except for a common epitope, but is instead 71% identical to human splicing factor PSF within a 320 aa region that includes both RRMs. In addition, both p54nrb and PSF are rich in Pro and Gln residues outside the main homology region. The Drosophila puff-specific protein BJ6, one of three products encoded by the alternatively spliced no-on-transient A gene (nonA), which is required for normal vision and courtship song, is 42% identical to p54nrb in the same 320 aa region. The striking homology between p54nrb, PSF, and NONA/BJ6 defines a novel phylogenetically conserved protein segment, termed DBHS domain (for Drosophila behavior, human splicing), which may be involved in regulating diverse pathways at the level of pre-mRNA splicing.

The PRP18 gene, which had been identified in a screen for pre-mRNA splicing mutants in Saccharomyces cerevisiae, has been cloned and sequenced. Yeast strains bearing only a disrupted copy of PRP18 are temperature sensitive for growth; even at a low temperature, they grow extremely slowly and do not splice pre-mRNA efficiently. This unusual temperature sensitivity can be reproduced in vitro; extracts immunodepleted of PRP18 are temperature sensitive for the second step of splicing. The PRP18 protein has been overexpressed in active form in Escherichia coli and has been purified to near homogeneity. Antibodies directed against PRP18 precipitate the U4/U5/U6 small nuclear ribonucleoprotein particle (snRNP) from yeast extracts. From extracts depleted of the U6 small nuclear RNA (snRNA), the U4 and U5 snRNAs can be immunoprecipitated, while no snRNAs can be precipitated from extracts depleted of the U5 snRNA. PRP18 therefore appears to be primarily associated with the U5 snRNP. The antibodies against PRP18 inhibit the second step of pre-mRNA splicing in vitro. Together, these results imply that the U5 snRNP plays a role in the second step of splicing and suggest a model for the action of PRP18.

This is an annotated collection of the minutes of a thriving Ku Klux Klan in La Grande, Oregon, between 1922 and 1924. The most complete set of Klan minutes ever uncovered, these documents illustrate the inner workings of a Klan chapter of more than 300 members at the time when the national membership reached into the millions and the Invisible Empire was at the peak of its power. Through an extensive introduction and conclusion as well as brief notes previewing each installment of the minutes, the author seeks to place these documents in historical perspective. The La Grande minutes demonstrate Klan hostility to Roman Catholics, Jews, blacks and "hyphenated" Americans. But they also explain how the chapter exercised requirements for admission, how officers were selected, and how Klansmen encountered difficulties enforcing the moral standards of their order. Because the Klan kligrapp (recording secretary) Harold R. Fosner recorded not only the official proceedings but also volunteered extemporaneous comments and gossip, readers should get a feeling for what it was like to attend the meetings. Horowitz concludes that "although it is tempting to judge Jazz Age Klansmen by the standards of later generations, the story provided by the minutes is a complex one - a chronicle of both compassion and complicity in cruelty, of positive social accomplishment and arbitrary and dysfunctional divisiveness".

• Systemic corticosteroids may be either contraindicated or not efficacious in treating the cutaneous manifestations occurring in 20% to 35% of patients with systemic sarcoidosis. Chloroquine phosphate has been reported to be a valuable alternative therapy for cutaneous lesions of sarcoidosis. With a judiciously determined daily dosage and regular 6-month ophthalmologic follow-up examinations, the risk of developing retinopathy can be avoided, because the daily dosage rate rather than total dose accumulation determines the development of chloroquine-induced retinopathy. We reviewed the efficacy and safety of chloroquine and its role in the treatment of cutaneous sarcoidosis. ( Arch Dermatol. 1991;127:1034-1040)

High-resolution nitrogen-15 NMR spectra of adenine have been obtained both at the S-adenosylmethionine level and for a uniformly enriched sample prepared from S-adenosylmethionine isolated from yeast grown with ^(15)NH_4CI as the principal nitrogen source. Specific ^(15)N labeling at N1, N3, N6’, N7, and N9 provided unequivocal assignments of the chemical shifts as well as elucidation of the position of the tautomeric equilibrium. For comparison, the nitrogen resonances of several adenine derivatives were determined at the natural-abundance level. The protonation sites of many of these substances were determined from the effect of pH on the nitrogen chemical shifts. Both adenine and its conjugate acid clearly exist as the N9-H tautomers in aqueous solution. Conversion of adenine to its conjugate base (pK, ~ 10) results in a 56 ppm downfield shift of the N9 resonance.

Sexual abuse of children has come to the forefront of our national consciousness through continued exposure in newspapers, in magazines, and on television. Despite this media attention, many pediatricians have not been trained to evaluate cases of suspected sexual abuse. Because estimates of the prevalence of sexual abuse in the general population range into the millions,1 it is likely that the office-based pediatrician will encounter more and more cases. Although guidelines for evaluation of child abuse exist,2 professional journals are now beginning to address sexual abuse. A recent article by Krugman3 reviewed the role of the office-based pediatrician in sexual abuse cases. Some points that he discussed included maintaining a high index of suspicion for both direct and masked presentations of sexual abuse; interviewing skills needed for both the child and family; legal ramifications; and the need for a coordinated effort among the many groups of professionals involved in each case, in an effort to minimize separate, repetitive, and traumatic evaluations. This article is intended to supplement Krugman's by providing a detailed description of the vaginal examination of the prepubertal child and adolescent. PHYSICAL EXAMINATION The prerequisite of a thorough, sensitive examination is time. This is the one element most lacking in a busy office or emergency room. Preparing the child for the examination will take more time the examination itself; this preparation is the most important part of the examination process. PHYSICAL EXAMINATION The prerequisite of a thorough, sensitive examination is time. This is the one element most lacking in a busy office or emergency room. Preparing the child for the examination will take more time than the examination itself; this preparation is the most important part of the examination process.

Social scientists have contributed to educational policy, but they can do more.

By analyzing the Boltzmann populations of DNA topoisomers that differ only in their linking numbers, the dependence of the free energy delta G tau of DNA supercoiling on the linking number alpha has been determined for DNA rings as small as 200 base-pairs (bp) in length. All experimental data can be fitted by the relation delta G tau = K (alpha-alpha)2, where alpha is a constant for a given DNA at a given set of conditions and K is a DNA length-dependent proportionality constant. For DNA rings with length N larger than 2000 bp, K is inversely proportional to N and the product NK is nearly a constant around 1150 RT X bp. For rings smaller than 2000 bp NK increases steadily with decreasing N; for a 200 bp ring NK is 3900 RT X bp. The increase in NK when N decreases can be interpreted as a result of the decrease in the contribution of the fluctuation in the writhing number to the equilibrium distribution in alpha. Assuming that the writhing contribution approaches zero for DNA rings 200 bp in size, the torsional rigidity of the DNA double helix is calculated to be 2.9 X 10(-19) erg cm. In addition, the large value of K for the small circles allows precise calculation of the helical repeat of DNA. For the 210 bp rings, the repeat is measured to be 10.54 bp.