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Objective: To increase accrual among Hispanics to the Cancer Genetics Network national cancer genetics registry., Methods: Drawing from South Texas cancer registries, 444 Hispanic men and women were randomly assigned to one of three experimental conditions: standard direct-mailed procedures (X1), X1 plus culturally tailored materials (X2), and X2 plus interpersonal phone contact (X3). Participants were also surveyed about the effectiveness of the education materials and the phone contact. A refusal survey was provided for those who declined to join the study., Results: A total of 154 individuals joined the Cancer Genetics Network. The X3 condition yielded the greatest accrual (43.2%) compared to X1 (30.9%) and X2 (29.9%; p < 0.05). Tailored materials appeared to have no effect but were highly regarded. The main reasons for not participating were a lack of interest and time requirements., Conclusion: Interpersonal communication can have a powerful effect on recruitment. However, more research is needed to determine the cost-efficacy of more labor-intensive approaches to registry accrual., (Copyright 2008 S. Karger AG, Basel.)

Background: Many definitions are being used to conceptualize child health problems. With survey data, commonly used indicators for identifying children with health problems have included chronic condition checklists, measures of activity limitations, elevated service use, and health utility thresholds. This study compares these different indicators in terms of the prevalence rates elicited, and in terms of how the subgroups identified differ., Methods: Secondary data analyses used data from the National Longitudinal Survey of Children and Youth, which surveyed a nationally representative sample of Canadian children (n = 13,790). Descriptive analyses compared healthy children to those with health problems, as classified by any of the key indicators. Additional analyses examined differences between subgroups of children captured by a single indicator and those described as having health problems by multiple indicators., Results: This study demonstrates that children captured by any of the indicators had poorer health than healthy children, despite the fact that over half the sample (52.2%) was characterized as having a health problem by at least one indicator. Rates of child ill health differed by indicator; 5.6% had an activity limitation, 9.2% exhibited a severe health difficulty, 31.7% reported a chronic condition, and 36.6% had elevated service use. Further, the four key indicators captured different types of children. Indicator groupings differed on child and socio-demographic factors. Compared to children identified by more than one indicator, those identified only by the severe health difficulty indicator displayed more cognitive problems (p < 0.0001), those identified only by the chronic condition checklist had a greater likelihood of reporting allergies or asthma (p < 0.0001), and those identified as having elevated service use only were more affluent (p = 0.01) and showed better overall health (p < 0.0001). Children identified by only a single indicator were less likely to have serious health problems than those identified by two or more indicators., Conclusion: We provide information useful to researchers when selecting indicators from survey data to identify children with health problems. Researchers and policy makers need to be aware of the impact of such definitions on prevalence rates as well as on the composition of children classified as being in poor health.

We explored the mechanical factors leading to the formation of labral tears and the effect of these lesions on hip kinematics at the extremes of joint motion. Using a 3D motion analysis system, the stability of six cadaveric hips was measured during loading maneuvers known to impose anterior loads on the joint margin. These measurements were repeated following venting of the capsule, and after creation of a 15-mm tear in the intact labrum. Compared to the intact hip, 43% and 60% less force was required to distract the femur by 3 mm after venting and creation of a tear. An ER torque of 177 in-lbf in 30 degrees of flexion caused the vented and torn specimens to rotate 1.5 degrees +/- 2.7 degrees and 7.1 degrees +/- 4.7 degrees more than the intact specimen, and the femoral head to displace 1.21 +/- 0.53 mm and 0.67 +/- 0.35 mm, respectively. A breach of the integrity of labral function is shown to lead to decreased femoral stability relative to the acetabulum during extreme ranges of motion.

Purpose: To determine the functional and cosmetic outcomes of combined iris reconstruction lens (Ophtec) implantation and penetrating keratoplasty (PK) in eyes with acquired partial or complete aniridia., Setting: Jules Stein Eye Institute and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA., Methods: In a prospective nonrandomized single-center interventional case series, efficacy measures included improvement in cosmesis and reduction in glare, star bursts, and photophobia. Safety measures included changes in best corrected visual acuity (BCVA), reports of adverse events, and surgical complications., Results: The 9 eyes in the study had a history of penetrating or blunt trauma and were aphakic or in need of cataract surgery. Corneal pathologies necessitating transplantation included scarring, decompensation, or failure of a previous graft. Postoperatively, all patients were pleased with the cosmetic improvement of the study eye and all reported a reduction in visual disturbances. By the final follow-up examination, the BCVA improved in 4 patients but worsened in 5. Three adverse events were reported. There were no intraoperative surgical complications. The most serious postoperative complications were a pressure spike leading to loss of light perception, corneal graft rejection, and graft failure. The most common postoperative problem was surgically induced irregular corneal astigmatism., Conclusions: Ophtec iris reconstruction lens implantation and simultaneous PK reduced visual disturbances and improved the aesthetic appearance of the eyes. The long-term safety of the procedure, judged by BCVA and postoperative complications, was mixed, with both good and bad outcomes.

Canadian research on health services for children and youth with chronic health conditions (CHC) is limited. In a postal survey, pediatricians in British Columbia rated the quality and safety of health care services for children with chronic medical conditions (Ch-Med) lower (mean rating +/- SD on a seven-point scale: 4.86 +/- 1.02 ) than services for children with acute conditions/injuries (5.97 +/- 1.01), and lowest for children with chronic developmental, behavioral and mental health conditions (Ch-DBM; 3.06 +/- 1.17). To improve health care services for CHC, respondents especially favoured improving access to community-based services and resources and to medical specialists and specialized facilities, and the implementation of alternative models of care. Respondents indicated that physician care of children with CHC could be enhanced by extending the physician's role, better integrating medical with other aspects of care and adopting more flexible payment mechanisms. Findings suggest the need for enhancement and innovation in medical services for children with CHC, especially Ch-DBM, but also that solutions need to take account of CHC subcategory, geographic factors and differences in practitioner readiness to embrace change.

PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.

The tremendous increase in the global prevalence of Type 2 diabetes (T2D) and its conglomeration of metabolic disorders has dramatically intensified the search for innovative therapies to fight this emerging epidemic. Over the last decade, the family of nuclear receptors, especially the peroxisome proliferator-activated receptors (PPARs), has emerged as one of the most important drug targets aimed at combating the metabolic syndrome. Consequently, compounds that activate the PPARs have served as potential therapeutics for the treatment of T2D and the metabolic anomalies associated with this disorder. This review focuses on the currently marketed compounds and also describes the discovery and development of the next generation of PPAR ligands that are under investigation for the potential treatment of T2D and the metabolic syndrome.

A method for the determination of a prostaglandin D(2) receptor antagonist (I, a compound being evaluated for the prevention of niacin induced flushing) and its acyl glucuronide metabolite (II) in human plasma is presented. The method utilized high performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection using an atmospheric pressure chemical ionization (APCI) interface operated in the positive ionization mode. The product ion was a radical cation generated via a homolytic bond cleavage. A chemical analog of the drug was used as internal standard (III). The acyl glucuronide metabolite (II) was detected using the same precursor-to-product ion transition used for the parent compound after chromatographic separation of I and II. Drug and metabolite were extracted using semi-automated, 96-well format solid phase extraction (SPE), and chromatography was performed using a reverse phase analytical column with an isocratic mobile phase. The chromatographic retention factor (k') of II was found to be highly sensitive to mobile phase formic acid concentration. An adjustment in mobile phase formic acid concentration improved the chromatographic separation between II and a mono-hydroxylated metabolite after an unexpected lack of MS/MS selectivity between the two molecules was observed. The dependence of retention factor on formic acid concentration (k' increased as formic acid concentration decreased) was thought to indicate polar interactions between II and the stationary phase. The stability of II in spiked human plasma was determined. The rate of hydrolysis back to parent compound was relatively low (approximately 0.1 and 0.5% per hour at room temperature and 4 degrees C, respectively) indicating that significant changes in analyte concentrations did not occur during sample processing. The concentration range of the assay was 10-2500 ng/mL for both drug and glucuronide metabolite.

Background: Keloids are common benign tumors of the dermis, typically arising after insult to the skin. While typically only impinging on cosmesis, large or recurrent keloids may require therapeutic intervention. While no single standardized treatment course has been established, several series report excellent outcomes for keloids with post-surgery radiation therapy., Case Presentation: We present a patient with a history of recurrent keloids arising in the absence of an ascribed trauma and a maternal familial history of keloid formation, whose physical examination several large perineal keloids of 6-20 cm in the largest dimension. The patient was treated with surgical extirpation and adjuvant radiation therapy. Radiotherapy was delivered to the scar bed to a total dose of 22 Gy over 11 daily fractions. Acute radiotherapy toxicity necessitated a treatment break due to RTOG Grade III acute toxicity (moderate ulceration and skin breakdown) which resolved rapidly during a 3-day treatment break. The patient demonstrated local control and has remained free of local recurrence for more than 2 years., Conclusion: Radiotherapy for keloids represents a safe and effective option for post-surgical keloid therapy, especially for patients with bulky or recurrent disease.

Objective: To provide a preliminary description of the interest, awareness, and perceptions of genetic testing among Hispanics with a family history of breast cancer, Design: This cross-sectional pilot study used interpersonal structured interviews for data collection., Participants: We interviewed 48 Hispanics without breast cancer but who had a family member with breast cancer; participants lived in San Antonio and the surrounding area., Main Outcome: The outcomes were interest in breast cancer genetic testing, awareness about genetic testing, perceived risk of carrying a breast cancer susceptibility gene, and the perceived benefits and risks associated with a genetic test., Measures: Items previously used in research regarding interest and perceived genetic risk and a previously validated benefits and risks-limitations scale for genetic testing commonly used by other researchers were used to measure the outcomes., Results: Awareness of genetic testing for breast cancer susceptibility was very low, yet most (82%) participants were interested in a genetic test for breast cancer susceptibility. Participants were more likely to identify with the benefits than the potential risks of genetic testing. The most highly endorsed benefits were to know to take better care of one's self and to undergo more frequent screening., Conclusions: Hispanics seem to have positive perceptions about genetic testing for breast cancer susceptibility. However, the high level of interest in genetic testing may be driven by a lack of knowledge about genetic testing. Culturally sensitive and appropriate educational programs about breast cancer genetic testing and the surrounding issues are needed for the Hispanic population.

The measurement of antioxidant capacity in fruits differs from that of other biological samples due to their low pH and very low lipophilic antioxidant capacity. In this report, we present a modified 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method for fruits and compare its performance with the other commonly used antioxidant methods of 2,2'-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP). The antioxidant capacity and reaction kinetics of four phenolic compounds, two antioxidant standards, and five fruits were also investigated. The modified ABTS method prepared at a pH of 4.5 with sodium acetate buffer is highly stable and easily applied to fruit samples as compared to the standard (pH 7.4) version. The measured antioxidant capacity of samples varied with the assay method used, pH, and time of reaction. Traditional antioxidant standards (trolox, ascorbic acid) displayed stable, simple reaction kinetics, which allowed end point analysis with all of assays. Of the phenolic compounds examined, chlorogenic and caffeic acids exhibited the most complex reaction kinetics and reaction rates that precluded end point analysis while gallic acid and quercetin reached stable end points. All fruit extracts exhibited complex and varied kinetics and required long reaction times to approach an end point. Because the antioxidant capacity of fruit extracts is a function of the array of individual antioxidants present, accurate comparisons among fruit samples require that reaction times be standardized and of sufficient length to reach steady state conditions and that more than one assay be used to describe the total antioxidant activity of fruit samples.

Purpose: Carrier prediction models estimate the probability that a person has a BRCA mutation. We evaluated the accuracy of the BOADICEA model and compared its performance with that of other models (BRCAPRO, Myriad I and II, Couch, and Manchester Scoring System). We also studied the effect of extended family information on risk estimation using BOADICEA., Methods: We compared the area under receiver operating characteristic curves generated from 472 families with one member tested for BRCA mutations. We calculated sensitivity, specificity, and predictive values at an estimated probability of 10% and explored the biases of carrier prediction., Results: BOADICEA performed better than the other models in Ashkenazi Jewish (AJ) families, BRCAPRO performed slightly better in non-AJ families, and Myriad II performed comparably well in both groups. Including extended family information in BOADICEA yielded slightly better performance than did limiting the information to second-degree relatives. Using a 10% cutoff point, BOADICEA and Myriad II were most sensitive in predicting BRCA1/2 mutations in AJ families, and Myriad II was most sensitive in non-AJ families. The Manchester Scoring System was the most sensitive and least specific in a subgroup of non-AJ families. BOADICEA and BRCAPRO tended to underestimate the observed risk at low estimated probabilities and overestimate it at higher probabilities., Conclusion: The BOADICEA, BRCAPRO, and Myriad II models performed similarly. Including second-degree relatives slightly improved carrier prediction by BOADICEA. The Myriad II model was the easiest to implement.

Creatine phosphokinase (CPK) estimations are done routinely in some HIV clinics, irrespective of patient symptoms. We studied patients attending the Worcestershire HIV clinic between 1987 and 2001 to identify whether routine elevations in serum levels of CPK in patients with HIV were associated with clinical features of muscle disease (CFMD), and whether such elevations influenced patient management. There was no association between CFMD and a rise in CPK. Major rises of CPK >400 IU/L were significantly associated with CFMD. No individual had a persistent CPK rise >200 IU/L without CFMD. In the great majority of cases, there was no change in management consequent to enzyme rises. In patients with HIV infection and no CFMD, the chance of finding a major and persistent CPK rise is low. This study does not support the practice of routine monitoring of CPK in asymptomatic patients attending HIV clinics.

BACKGROUND: Gangliocytic paraganglioma are rare neoplasms that predominantly arise in periampulary region. Though considered benign the disease can spread to regional lymphatics. CASE PRESENTATION: A 49 year old woman presented with melena and was found to have a periampullary mass. Endoscopic evaluation and biopsy demonstrated a periampullary paraganglioma. The tumor was resected with pylorus-preserving pancreaticoduodenectomy and was found to represent a gangliocytic paraganglioma associated with nodal metastases. In a controversial decision, the patient was treated with adjuvant external beam radiation therapy. She is alive and well one year following resection. The authors have reviewed the current literature pertaining to this entity and have discussed the biologic behavior of the tumor as well as the rationale for treatment strategies employed. CONCLUSION: Paraganglioma is a rare tumor that typically resides in the gastrointestinal tract and demonstrates low malignant potential. Due to rarity of the disease there is no consensus on the adjuvant treatment even though nearly 5% of the lesions demonstrate the malignant potential.

Objective: To examine persistence with methylphenidate (MPH) therapy among children and youth in the general population., Method: We conducted a retrospective analysis of longitudinally organized, individual-specific anonymous data from linked prescription and health databases covering the population of British Columbia for 1990 through 1996. No prescriptions being filled for 4 months indicated cessation of one bout of therapy., Results: Among 16,945 identified MPH patients aged 19 years or under, overall duration of therapy was 584 days, and the average number of prescriptions received was 6.6. One-third of patients received 2 or fewer prescriptions, while 18% followed a chronic, continuous course. Among patients receiving more than 2 prescriptions, 50% of discrete therapy bouts lasted 4 months or less, and one-third of cases had multiple bouts of therapy (range 2 to 6 bouts). Younger age (that is, children aged 0 to 8 years, vs those aged 10 to 19 years), male sex, and receipt of initial prescription from a psychiatrist were associated with greater persistence., Conclusions: Enormous variability in persistence with MPH therapy and often-occurring low rates of persistence raises questions about the diligence with which MPH patients are selected, prepared, and followed in the general population. Special attention to the needs of older children and to the needs of girls is required, and discontinuities during children's therapy courses require explication.

Background and Objectives: Histologic margin positivity represents a significant source of adverse clinical outcome affecting breast conservation therapy for in situ or invasive malignancy. Elucidation of factors associated with positive margin status might clarify and improve local therapy strategies. In order to define our experience with margin positivity and to identify relevant pathologic criteria, we retrospectively analyzed the cases of 143 patients who underwent resections for carcinoma with intent of breast conservation between 1995 and 1999., Methods: Histologic features and indices of biologic aggressiveness were compared among tumors resected with positive versus negative margins in order to determine whether such markers could be used to anticipate outcome., Results: Twenty-eight pathologic specimens were identified to possess histologically positive margins. Twenty-six patients underwent additional operative procedures. Of the 26 re-excision specimens, 17 (65%) contained residual malignancy. Statistical analysis demonstrated that margin positivity correlated with in situ histology and with Her 2/neu positivity., Conclusions: These data suggest certain pathologic factors that may portend difficulty in achieving negative resection margins in patients in whom breast conservation therapy is considered., (Copyright 2004 Wiley-Liss, Inc.)

The metabolism, excretion, and pharmacokinetics of caspofungin (Cancidas; Merck & Co., Inc.) were investigated after administration of a single intravenous dose to mice, rats, rabbits, and monkeys. Caspofungin had a low plasma clearance (0.29 to 1.05 ml/min/kg) and a long terminal elimination half-life (11.7 h to 59.7 h) in all preclinical species. The elimination kinetics of caspofungin were multiphasic and displayed an initial distribution phase followed by a dominant beta-elimination phase. The presence of low levels of prolonged radioactivity in plasma was observed and was partially attributable to the chemical degradation product M0. Excretion studies with [(3)H]caspofungin indicated that the hepatic and renal routes play an important role in the elimination of caspofungin, as a large percentage of the radiolabeled dose was recovered in urine and feces. Excretion of radioactivity in all species studied was slow, and low levels of radioactivity were detected in daily urine and fecal samples throughout a prolonged collection period. Although urinary profiles indicated the presence of several metabolites (M0, M1, M2, M3, M4, M5, and M6), the majority of the total radioactivity was associated with the polar metabolites M1 [4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine] and M2 [N-acetyl-4(S)-hydroxy-4-(4-hydroxyphenyl)-L-threonine]. Caspofungin was thus primarily eliminated by metabolic transformation; however, the rate of metabolism was slow. These results suggest that distribution plays a prominent role in determining the plasma pharmacokinetics and disposition of caspofungin, as very little excretion or biotransformation occurred during the early days after dose administration, a period during which concentrations in plasma fell substantially. The disposition of caspofungin in preclinical species was similar to that reported previously in humans.

As the incidence of Type 2 diabetes has reached near epidemic proportions, the quest for novel therapies to combat this disorder has intensified dramatically. In recent years, the peroxisome proliferator-activated receptor (PPAR) family has received tremendous attention as perhaps an ideal target class to address the multiple metabolic anomalies associated with the diabetic state. This review focuses on a variety of novel PPAR approaches currently being investigated for Type 2 diabetes or the metabolic syndrome, including the highly potent selective PPAR agonists, PPAR combination agonists and alternative PPAR ligands.

Testicular cancer metastasis to the retroperitoneum can be associated with a variety of complications due to obstruction or invasion of adjacent structures. In this case report, we present an unusual patient with invasion of the duodenum from germ cell cancer and discuss the management of this challenging scenario.

The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.

Context: Management of breast needle core biopsies diagnosed as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ is controversial. Current recommendations involve excisional biopsy to rule out ductal carcinoma in situ and/or invasive carcinoma, which have been reported in more than 50% of cases in some series., Objective: To determine how frequently these diagnoses made on needle core biopsy are ultimately found to represent in situ or invasive carcinoma based on excisional biopsy specimens, in order to identify predictive factors., Design: One thousand eight hundred thirty-six image-guided needle core biopsies were performed between January 1, 1995 and May 1, 2001. Fifty-four (2.9%) patients diagnosed with atypical ductal hyperplasia (n = 36), atypical lobular hyperplasia (n = 12), atypical ductal hyperplasia + atypical lobular hyperplasia (n = 3), or lobular carcinoma in situ (n = 3) subsequently underwent breast excisions. Pathologic features were reviewed in each of the needle core biopsies using Page's criteria and were then correlated with excision specimens., Setting: University medical center., Results: Review of the needle core biopsy cases with either ductal carcinoma in situ or invasive carcinoma + ductal carcinoma in situ on final excision showed that nucleoli were evident in most of the needle core cases, with foci of nuclear pleomorphism and individual cell necrosis or apoptosis., Conclusion: A more precise diagnosis can be made by using strict criteria for atypical ductal hyperplasia versus ductal carcinoma in situ on needle core biopsy. Cytologic atypia, even if in a small area, particularly when there is apoptosis/individual cell necrosis, correlates with the finding of a more serious lesion on excision.

Purpose: Because survival in patients with locally recurrent rectal cancer (LRRC) is limited, pain control and quality of life (QOL) are important parameters. The purpose of this study was to assess the prevalence of posttreatment pain and QOL of patients with LRRC treated with nonsurgical palliation or resection and identify predictors of poor outcome., Patients and Methods: Posttreatment pain severity and QOL were prospectively assessed in 45 patients with LRRC using the Brief Pain Inventory and Functional Assessment of Cancer Therapy-Colorectal questionnaire., Results: Fifteen patients received nonsurgical palliation, and 30 patients underwent resection of their pelvic tumors. There was a significant association between higher posttreatment pain scores and worse QOL (P <.001). Patients treated with nonsurgical palliation reported moderate to severe pain beyond the third month of treatment. Resected patients reported comparable levels of pain during the first 3 postoperative years, particularly after bony resections; long-term survivors (beyond 3 years), however, reported minimal pain and good QOL. Female sex, pelvic/sciatic pain at presentation, total pelvic exenteration, and bony resection were associated with higher rates of moderate to severe posttreatment pain (P =.04, P <.001, P =.04, and P =.02, respectively). Pain at presentation was an independent predictor of posttreatment pain (odds ratio, 7.4 [95% confidence interval, 1.8 to 30.3]; P =.006)., Conclusion: Patients with LRRC treated with nonsurgical palliation or resection experience significant levels of pain after treatment. Close posttreatment pain monitoring is warranted in patients presenting with pelvic pain, and more aggressive pain management strategies may improve posttreatment QOL.

Background: Sentinel lymph node mapping (SLNM) and neoadjuvant chemotherapy are becoming established components of therapy for selected patients with breast carcinoma. However, neoadjuvant therapy has been considered a relative contraindication to SLNM. In an effort to learn whether patients who have received preoperative chemotherapy can undergo accurate SLNM, we evaluated our experience with this technique., Methods: From January 1997 to June 2000, SLNM and axillary lymph node dissection were concurrently performed in 35 patients who received preoperative chemotherapy. Mapping was performed with (99m)Tc sulfur colloid only in one patient and Lymphazurin dye only in 15 patients, and the two methods were combined in the remainder., Results: SLNM successfully identified a sentinel lymph node in 30 (86%) patients. Metastatic disease was identified in the sentinel lymph nodes of four patients during surgery. The intraoperative pathologic diagnosis proved to be correct in 19 (79%) of 24 patients. The final pathologic diagnosis of the sentinel lymph node reflected the status of the axillary contents in all patients in whom it was identified., Conclusions: These results demonstrate that SLNM can be consistently performed in patients receiving preoperative chemotherapy for breast cancer, suggesting the utility of this technique in this patient population.

Background: Pancreatic carcinoma resists chemotherapeutic mediation of apoptosis. Irofulven (MGI 114, 6-hydroxymethylacylfulvene) is a novel illudin S analogue that we have shown to induce caspase-mediated apoptosis in pancreatic carcinoma cell lines., Materials and Methods: Westem blot analysis and kinase assays were used to demonstrate the activation of Erk 1/2 and JNK1 kinases following Irofulven administration in the presence and absence of selective kinase inhibitors., Results: Irofulven activates JNK1 and Erk1/2, but not p38. The addition of the MAPK inhibitors, SB202190 and PD98059 (targeting JNK1 and Erk1/2 activation, respectively), prevents kinase activation and blocks Irofulven-induced activation of caspases -3, -7, -8 and -9. Blockade of either JNK1 or Erk1/2 results in a 50% decrease in apoptosis in MiaPaCa-2 cells treated with Irofulven., Conclusion: Our data demonstrated that JNK1 and Erk1/2 are activated by Irofulven treatment and that blockade of either MAPK subfamily decreases apoptosis by rendering Irofulven incapable of inducing caspase activation.

Background: There are concerns about the frequency and appropriateness of psychostimulant drug prescription to children. In order to identify unusual or unexpected patterns of use or prescribing, we reviewed prescription of methylphenidate (Ritalin) to children and adolescents aged 19 years or less in British Columbia between 1990 and 1996., Methods: We obtained information about patients, physicians and prescriptions from British Columbia's Triplicate Prescription Program database for controlled drugs. Prescription data were available for the period Jan. 1, 1990, to Dec. 31, 1996. Linkage with the BC Linked Health Dataset provided additional demographic and health information., Results: In 1990, 1715 children received at least 1 prescription for methylphenidate (1.9 per 1000 children). By 1996, the number had increased to 10,881 children (11.0 per 1000). Because some children were prescribed methylphenidate in more than 1 year, we also calculated the frequency with which the drug was prescribed to children who had never received it before. This rate increased from 1.0 per 1000 children in 1990 to 4.7 per 1000 in 1995; the rate fell in 1996 to 3.5 per 1000. The number of children receiving methylphenidate varied across health regions of the province, from 12.0 to 35.4 per 1000. Use also varied by socioeconomic status quintile: in the 2 lowest (least privileged) quintiles, 21.6 per 1000 children received methylphenidate, compared with 18.4 per 1000 in the 3 highest quintiles (relative risk 1.2, 95% confidence interval 1.1-1.2). Pediatricians and psychiatrists wrote 23% and 21% of all prescriptions respectively. General practitioners accounted for 56% of all prescriptions and 41% of initial methylphenidate prescriptions. A claim for prior specialist consultation was found in 30% of such cases. Many of the children who received more than 10 prescriptions had seen 4 or more physicians. The average daily dosage prescribed differed little among general practitioners, pediatricians and psychiatrists, unlike the mean interval between successive prescriptions: 89.9 (standard deviation [SD] 68.2), 99.8 (SD 64.1) and 75.9 (SD 70.2) days respectively. Persistence with therapy was more likely when a psychiatrist provided the initial prescription, or with involvement of more than one specialty., Interpretation: Many trends and practices in the prescription of methylphenidate to children in British Columbia are consistent with other settings and accepted standards. Some aspects warrant closer investigation, including regional and socio-economic discrepancies in the distribution of patients, the relative involvement of primary and specialist care providers, continuity of care issues and time intervals between prescriptions.

Background: Irofulven (MGI 114) is a novel, clinically active sesquiterpene whose mechanism of action is not fully understood. We sought to identify apoptotic effectors induced by this agent in human pancreatic cancer cells., Materials and Methods: MTT assay was used to assess IC50-Apoptosis was quantitated by flow cytometry and DAPI staining. Caspase activation was identified by western blot analysis., Results: Irofulven was cytotoxic against all pancreatic cancer cell lines tested (IC50 1-18 microM), and induced 10-fold (4%+/- 2, vs. 41% +/- 5) induction of apoptosis. Irofulven-treated cells also demonstrated PARP3 cleavage and DAPI staining. Apoptosis was reduced to baseline levels by Z-VAD-FMK, a broad-spectrum caspase inhibitor. Western blot analysis revealed that caspases-3, -7, -8, and -9 were activated by irofulven. Time course evaluation demonstrated that caspases-8 and -9 were the initial species activated., Conclusion: Our data demonstrate that the cytotoxicity of irofulven in human pancreatic carcinoma cell lines is mediated by caspase-induced apoptosis.

The potential efficacy of prodrug activation of a transduced suicide gene in a cancer cell may be impaired or enhanced by oncoproteins produced by that cell. In the context of a gene therapy protocol for chronic myeloid leukemia (CML) we examined whether the Bcr-Abl fusion protein would have either of these effects. Thus, the mechanism of cell killing by transfer of herpes simplex virus thymidine kinase (HSV-tk) and subsequent ganciclovir (GCV) treatment was examined in pre-B (TonB210.1) cells and myeloid cells (32D) and in their BCR-ABL-expressing counterparts. HSV-tk-transduced cell lines, either in the presence or in the absence of BCR-ABL expression, became susceptible to GCV at concentrations which were nontoxic to the nontransduced cells. This susceptibility was represented by apoptotic cell death in all cases. Apoptosis was observed after 24 h of treatment with GCV in the tk-transduced parental cells and in the BCR-ABL-expressing TonB210.1 cells but only after a delay of more than 24 h in the 32Dp210 cells compared to 32D. Cell death in the BCR-ABL-expressing clones was preceded by S- and G2/M-phase cell cycle arrest. Activation of FAS/APO-1 and caspase-8 was observed in all the tk-transduced cell lines after GCV treatment. However, the caspase-8 inhibitor Z-IETD-FMK only partially abrogated tk/GCV-induced apoptosis. A possible role for inhibition of Bcl-2 or Bcl-x(L) expression in the apoptosis induced by GCV was observed in the tk-transduced TonB210.1 cells but not in the 32D or 32Dp210 cells. The data demonstrate that expression of the Bcr-Abl oncoprotein does not block the apoptosis induced by the HSV-tk/GCV system, suggesting that this suicide gene therapy strategy could be considered for the treatment of CML in blast crisis.

Background and Objective: Irritable bowel syndrome (IBS) and somatization disorder (SD) are defined by nonobjective symptoms that overlap considerably. Psychiatric symptoms associated with IBS may originate from SD in IBS patients. Previous studies of IBS have not considered SD separately from IBS., Methods: This study explored psychiatric symptoms and illness behavior in IBS in relation to SD. A total of 50 outpatients with IBS or ulcerative colitis (UC) were evaluated with the Diagnostic Interview Schedule and Illness Behavior Questionnaire., Results: Definite or probable SD was diagnosed in no UC patients and in 42% of IBS patients (confirmed in 25% and lacking one symptom in another 17%). IBS patients with probable or definite SD, but not those without SD, reported more psychiatric symptoms and abnormal illness behaviors than did UC patients. SD accounted for the association of psychiatric symptoms with IBS., Conclusions: In this university-based office setting, the association of psychiatric features with IBS appears heterogeneous predicated on whether SD is present. Future studies of functional bowel diseases should distinguish between patients with and without SD to clarify its relationship to these disorders. Clinicians should consider whether patients with functional disorders have SD, a diagnosis that indicates specific clinical management strategies.

Two experiments are described in which the P300 component of the event-related potential was recorded during a modification of the Deese-Roediger-McDermott false-memory paradigm. P300 amplitudes and topographies were evaluated in both true recognition of previously presented (studied) words and in false recognition of associatively related, never presented (critical lure) words. P300 topography and amplitude did not appear to differ between true and false recognition. However, false recognition of critical lures produced substantially shorter P300 latencies than did the true recognition of studied words.

A 49-year-old patient with primary, recurrent melanoma on the lower extremity developed metastatic leptomeningeal melanoma that did not respond to treatment with radiation therapy or intrathecal interleukin 2 (IL-2). Disease was characterized by neurological symptoms, including loss of hearing, loss of short-term memory, and gait disturbance. CD8+ CTLs were generated in vitro using autologous dendritic cells pulsed with peptides from the melanoma-associated antigens tyrosinase (145-156), Melan-A/MART-1 (26-35), and gp100/Pmel 17 (209-217). The CTLs exhibited up to 74% specific lysis against peptide-pulsed autologous EBV-transformed B cells, with Melan-A-specific CTLs yielding the greatest lytic activity. CD8+ CTLs possessed a type 1 cytokine profile, expressing tumor necrosis factor alpha and IFNgamma but not IL-4. Infusions of CTLs were supported with systemic low-dose IL-2 administration. 111In labeling and computerized gamma imaging were used to monitor the distribution of CTLs up to 48 h after infusion. Intra-arterial delivery via the right carotid artery was followed by redistribution of the CTLs to the lungs, liver, and spleen within 16 h. In contrast, delivery via an indwelling Ommaya reservoir resulted in prolonged retention of CTLs within the brain for at least 48 h after infusion. Marked but transient elevations in tumor necrosis factor alpha, IFN-gamma, and IL-6 in the cerebrospinal fluid were observed within 4 h of CTL infusion. There was no evidence of tumor progression throughout the treatment period, and clinically the patient showed some resolution of neurological symptoms.

Purpose: This study was performed to determine the quality of life and cost-effectiveness of therapeutic options for patients with locally recurrent rectal carcinoma, determined from the perspectives of patients and health care providers., Methods: We reviewed the records of patients (N = 68) with locally recurrent rectal carcinoma evaluated from 1992 through 1995. We constructed a decision-analytic model incorporating outcomes, survival, and costs. Utilities were elicited from convenience samples of health care providers and patients using the standard gamble technique., Results: The median survival for patients undergoing surgical resection (n = 40) was 42 months, compared with 16.8 months for patients undergoing diagnostic or palliative surgery (n = 16) and 18.3 months for patients treated nonoperatively (n = 12; P < 0.005). The mean cost of treatment per patient was $19,283 for the nonoperative group, $45,647 for the diagnostic or palliative surgery group, and $70,878 for the surgical resection group. The diagnostic or palliative surgical strategy was dominated by the nonoperative strategy because the former had greater costs with fewer health benefits. The incremental cost-utility ratio of surgical resection compared with nonoperative management using health care provider utilities was $109,777 per quality-adjusted life year gained; it was reduced to $56,698 using per quality-adjusted life year using mean patient utilities., Conclusions: Patients with recurrent rectal carcinoma view surgery and morbidity to be less severe than health care providers. Diagnostic or palliative surgery is expensive and affects quality-adjusted survival adversely compared with nonoperative therapy. Surgical resection may be a cost-effective use of resources, particularly when cost-effectiveness is calculated using patient preferences.

To evaluate the role of autocrine TNF-alpha signaling in macrophage activation, immortalized macrophages from normal mice (B6/J2) and from mice containing gene targeted disruptions of the type 1 and type 2 TNF-receptor genes (TRN) were stimulated under CD14-dependent or serum-free conditions. Although the B6/J2 and TRN clones mounted similar nitric oxide responses to LPS in the presence of serum, the TRN macrophages responded poorly when stimulated with LPS under serum free conditions. LPS stimulation of TRN and B6/J2 under serum-free conditions resulted in equivalent levels of IL-1beta, TNF-alpha, and iNOS gene expression. However, Western blot analysis revealed that iNOS protein production by TRN was 2-fold lower than that produced by B6/J2. These results indicate that autocrine TNF-alpha stimulation contributes to the signaling pathways initiated by ligation of LPS receptors in the absence of LBP and is involved in iNOS post-transcriptional regulation.

Thirty-four lactating Holstein cows were dried off 60 d prior to their expected calving date, paired by calving date, and randomly assigned to one of two photoperiod treatments: long-day photoperiod (n = 18; 16 h light: 8 h dark/d) or a short-day photoperiod (n = 16; 8 h light: 16 h dark/d) to determine if manipulation of photoperiod during the dry period would impact milk yield in the subsequent lactation. At parturition, calf weight, height, and length were measured and the cows were moved into ambient lighting conditions (November 1996 to January 1997 and November 1997 to January 1998, 39 degrees latitude) with the rest of the University of Maryland herd. After parturition, milk yield and composition were measured for 16 wk. Prolactin concentrations were higher by 11.7 ng/ml in the long-day photoperiod treatment group than for the cows on a short-day photoperiod. During lactation cows previously exposed to a short-day photoperiod produced 3.2 kg/d more milk than long-day photoperiod cows. Energy-corrected milk yield was greater in short-day photoperiod than in long-day photoperiod cows. Treatment did not affect calf growth, milk composition, or plasma insulin growth factor I concentrations. In conclusion, manipulation of photoperiod during the dry period of dairy cows may be a useful management tool for increasing milk yield in the subsequent lactation.

Replication-competent retrovirus (RCR) was identified in a GP+envAM12-derived producer cell, containing the MFG-S-Neo retroviral vector, using a marker rescue assay. Studies were undertaken to determine the origin and structure of this RCR. Receptor interference assays demonstrated that the virus was pseudotyped with an ecotropic envelope. Molecular analysis demonstrated the presence of a MoMLV ecotropic env recombinant where the neomycin resistance gene of the MFG-S-Neo vector was replaced by MoMLV ecotropic env. Additional recombinants linking the retroviral pol gene to neo and the neo gene to MoMLV env were also identified. A full-length MoMLV retroviral genome was detected by nested PCR in the contaminated amphotropic producer cells and in cells infected with its supernatant. Unexpectedly, this was also present in the GP+E86 packaging cells together with a previously undescribed envelope construct possessing a full 5' and 3' LTR, although these cells were consistently negative for the presence of RCR. These anomalies in the GP+E86 packaging cell line result in increased homology with the MFG-S-Neo vector, leading to an increased risk for the production of RCR. Our findings point to a need for increased vigilance when using these packaging lines to generate replication-defective retrovirus., (Copyright 2000 Academic Press.)

Autologous stem cell transplantation is a therapeutic alternative for many chronic myeloid leukaemia (CML) patients ineligible for the only curative treatment of allogeneic bone marrow transplantation. In this study the retroviral transduction of CD34+ progenitor cells isolated from the bone marrow (BM) and peripheral blood (PB) of patients with CML was compared to that of CD34+ cells isolated from the BM and PB of normal individuals and patients with non-haematological malignancies. A highly significant increase in transduction of all cell types was achieved in the presence of the recombinant fibronectin fragment, CH-296 (P < 0.05). In the absence of fibronectin, centrifugation produced a marginal improvement in the transduction of all cell types, which was significant only for CMLBM progenitor cells (P < 0.05). There was no significant additive effect when centrifugation was included in the fibronectin infection protocol. In the presence of CH-296, combinations of three or more cytokines improved transduction for all cell types. The same degree of transduction was observed for both normal and CML cells, irrespective of the variations employed in the infection protocol, suggesting that both leukaemic and non-leukaemic progenitors are equally susceptible to retroviral infection. These results demonstrate that CH-296 has a universal beneficial effect on the transduction of haemopoietic progenitor cells, with clear potential for future clinical trials.

Research was performed to demonstrate the removal of carbon tetrachloride (CT) using compost biofilters operated under methanogenic conditions. Biofilters were operated at an empty-bed residence time of 2.8 minutes using nitrogen as the atmosphere. Hydrogen and carbon dioxide were supplied as an electron donor and carbon source, respectively, during acclimation of the bed medium microbes. Once methanogenesis was demonstrated, CT flow to the biofilter was established. Biofilters were operated over a CT concentration range from 20 to 700 ppbv for 6 months. Bed medium microbes were able to remove up to 75% of the inlet CT. At excessively high CT concentrations (> 500 ppmv), methane production and hydrogen utilization by the bed medium microbes appeared to be inhibited. CT removal by the biofilter decreased when the hydrogen supply was removed from the biofilter inlet, indicating that hydrogen acted as the electron donor for reductive dechlorination. The removal efficiency and relatively low empty bed residence times demonstrated by these laboratory-scale biofilters indicate that anaerobic biofiltration of CT may be a feasible full-scale process.

An in vivo adenoviral gene delivery system was utilized to assess the effect of overexpressing protein kinase C (PKC)-zeta on rat skeletal muscle glucose transport activity. Female lean Zucker rats were injected with adenoviral/human PKC-zeta (hPKC-zeta) and adenoviral/LacZ in opposing tibialis anterior muscles. One week subsequent to adenoviral/gene delivery rats were subjected to hind limb perfusion. The hPKC-zeta protein was expressed at the same level (fast-twitch white) or at approximately 80% of the level (fast-twitch red) of endogenous PKC-zeta, thus approximately doubling the amount of PKC-zeta in tibialis anterior. Basal glucose transport activity was elevated approximately 3.4- and 2-fold, respectively, in fast-twitch white and red hPKC-zeta muscle relative to control. Submaximal insulin-stimulated glucose transport activity, corrected for basal transport, was approximately 90 and 40% over control values, respectively, in fast-twitch white and red hPKC-zeta muscle. The enhancement of glucose transport activity in muscle expressing hPKC-zeta occurred in the absence of any change in GLUT1 or GLUT4 protein levels, suggesting a redistribution of existing transporters to the cell surface. These results demonstrate that an adenoviral vector can be used to deliver expressible hPKC-zeta to adult rat skeletal muscle in vivo and also affirm a role for PKC-zeta in the regulation of glucose transport activity.

Bovine somatotropin (bST) and exposure to long daily photoperiod increase milk yield of dairy cattle. We tested the hypothesis that long daily photoperiod and bST treatment would increase milk yield in an additive manner in lactating cows. At winter solstice, 40 lactating cows were started on a 140-d experiment; cows were greater than 70 d in milk (DIM) and were balanced for uniformity of DIM and milk yield within parity. Cows were randomly assigned to one of four treatments (10/treatment): 1) natural photoperiod, 2) natural photoperiod + bST (14 mg/d Trobest i.m.), 3) long daily photoperiod (18 h of light and 6 h of darkness/d), or 4) long daily photoperiod + bST. Long daily photoperiod increased fat-corrected milk (FCM) yield 1.9 kg/d versus natural photoperiod. Treatment with bST increased FCM 5.7 kg/d versus natural photoperiod, and long daily photoperiod + bST increased FCM 5.8 kg/d versus long daily photoperiod. Long daily photoperiod + bST was additive, increasing FCM 7.7 kg/d versus natural photoperiod. Serum somatotropin increased with bST, but not photoperiod, and bST increased serum insulin-like growth factor-I. Long daily photoperiod tended to increase prolactin; bST had no effect. Long daily photoperiod + bST increased dry matter intake (DMI) relative to natural photoperiod and natural photoperiod + bST; long daily photoperiod increased DMI relative to natural photoperiod + bST. Photoperiod had no effect on net energy balance; however, bST decreased net energy balance. Generally, body weight and milk composition did not differ among treatments. In conclusion, combination of bST with long-daily photoperiod tended to amplify the increases in milk yield observed with either treatment individually.

Patients with somatization disorder (SD) endorse high rates of psychiatric symptoms. However, prior studies have not addressed whether these endorsed symptoms reflect underlying psychiatric illness or whether they represent symptom overendorsement mirroring somatic complaints in patients with SD. Thirty-two female outpatients with SD and 101 with other psychiatric disorders completed a checklist of current and lifetime psychiatric symptoms. These findings were analyzed with respect to the diagnoses given by their treating psychiatrists. Patients with SD displayed significantly more current and lifetime psychiatric symptoms than did patients without either SD or cluster B personality disorder. Patients with SD endorsed a large number of psychotic, manic, depressive, and anxiety symptoms; however, they endorsed few alcohol use disorder symptoms. Psychotic and manic symptoms endorsed by patients with SD did not reflect their clinical diagnoses: only two patients with SD carried an additional clinician diagnosis of either schizophrenia or bipolar disorder, despite high rates of endorsed symptoms by the group. Patients with cluster B personality disorders but without SD showed a symptom profile similar to that of patients with SD. Psychiatric outpatients with SD endorse many more psychiatric symptoms than do other psychiatric patients. Patients with SD in the psychiatric treatment setting may mimic other psychiatric illnesses; therefore, SD should be considered in the differential diagnosis for a wide variety of psychiatric illness, including psychotic and mood disorders.

Objective: To assess the frequency and clinical features of treatment-induced bowel injury in rectal carcinoma patients receiving perioperative external beam radiotherapy (EBRT). The frequency of and factors associated with treatment-induced intestinal injury have previously not been well quantified for rectal cancer patients. Postoperative adjuvant chemoirradiation is recommended for Stage II and III rectal cancers, making such data of significant interest., Methods and Materials: The records of 386 consecutive patients undergoing radiotherapy with or without chemotherapy (CT) for rectal carcinoma between 1981-90 were reviewed. Eight-two patients were excluded for receiving nontherapeutic EBRT or modalities other than EBRT., Results: Symptomatic acute treatment-related enteritis (within 30 days of EBRT +/- CT) was diagnosed in 13 patients, 3 of whom developed chronic bowel injury. Chronic treatment-related enteritis was identified in 18 patients and reoperation was required in 17 (5% of the 304 patients with complete follow-up). Chronic proctitis was documented in 38 patients, including 3 patients with small bowel injury. The probability of developing treatment-induced bowel injury at 5 years following treatment was 19%. Variables associated with an increased risk of bowel injury using multivariate analysis were transanal excision (p = 0.002), escalating radiation dose (p = 0.005), and increasing age (p = 0.01). Twenty of the affected patients required operative treatment, and 2 deaths resulted from treatment-induced enteritis., Conclusion: Patients with rectal carcinoma treated with EBRT +/- CT have the risk of developing treatment-induced bowel injury. The pelvic radiation dose should be limited to < or = 5040 cGy unless small bowel can be displaced. Reperitonealization of the pelvis, or other surgical methods of excluding the small intestine should be used whenever possible.

Isolated pelvic recurrence of rectal carcinoma may occur in up to one third of patients following definitive resection of primary disease. The means by which recurrence is diagnosed, methods by which it may be treated, and reported outcomes are all evolving and improving. Current data indicate that a substantial proportion of patients treated by aggressive multi-modality salvage therapy may be provided with durable survival. This review highlights current concepts in the diagnosis and management of locally recurrent rectal carcinoma.

Aims: To compare jejunal mucosal morphometry in HIV infected patients resident in London and Uganda., Patients: Twenty HIV positive patients from London and 16 from Uganda were studied, and compared with HIV negative control subjects from both sites., Methods: Stools and biopsy specimens were examined for enteropathogens. Surface area to volume (S:V) ratio was estimated morphometrically, mean crypt length of jejunal biopsy specimens was measured, and HIV infected cells detected immunohistochemically were quantified., Results: Enteric pathogens were detected in none of the London patients, and in three Ugandan patients. S:V ratio was lower, and mean crypt length higher, in the specimens of London patients than in normal subjects, but there was no difference in S:V ratio or mean crypt length between Ugandan patients and controls. A negative correlation was present between S:V ratio and mean crypt length in all biopsy specimens analysed. HIV infected cells were detected only in lamina propria., Conclusion: Infection of cells in the lamina propria of the jejunum with HIV stimulates crypt cell proliferation, and a fall in villous surface area. The mucosal response to HIV is masked by other pathogens in the African environment.

Meningococcal carriage and the immune response to colonization were studied in a group of military recruits undergoing basic training. Subtyping by determination of the class 1 protein sequence clearly differentiated between strains and demonstrated the dynamics of carriage and transmission. Expression of class 1 protein by each strain remained stable during prolonged carriage by different subjects. Following colonization, a marked increase in serum bactericidal response occurred, which was specific for the subtype of the acquired strain and was associated with an increase in reactivity by Western blot to the homologous class 1 protein. Subjects colonized by multiple strains showed evidence of a specific immune response to the class 1 protein of each strain acquired. The subtype specificity of the bactericidal response to meningococci and the stability of expression of the class 1 protein have important implications for the design of vaccines for prevention of serogroup B meningococcal disease.

The goal of multimodality therapy for localized pancreatic cancer is to maximize local-regional disease control and patient survival. In contrast to surgery for other solid tumors, prolonged recovery following pancreaticoduodenectomy may prevent the timely delivery of postoperative adjuvant therapy. Therefore, efforts at The University of Texas, M.D. Anderson Cancer Center have focused on the delivery of chemotherapy and radiation therapy prior to surgery in patients with localized pancreatic cancer. Clinical trials have emphasized the use of altered-fractionation schedules of radiation therapy combined with novel radiation-sensitizing agents. All treatment schemes aim to decrease toxicity and treatment time while improving therapeutic efficacy.